- Email: [email protected]
Lumbar Bone Mineral Density After Kidney Transplantation: A Three-Year Prospective Study
Lumbar Bone Mineral Density After Kidney Transplantation: A ThreeYear Prospective Study R. Marcén, C. Caballero, C. Galeano, J. Pascual, J. Ocaña, M. Tenorio, R. Echarri, G. Tabernero, J.J. Villafruela, F.J. Burgos, and J. Ortuño ABSTRACT Osteopenia is a common complication after transplantation. However, prospective long-term studies are scarce and most were performed in patients on cyclosporine and high-dose steroids. In 65 patients with functioning grafts, 41 males and 24 females, 50 on tacrolimus-based immunosuppression and 15 on cyclosporine-based immunosuppression, bone mineral density (BMD) was measured in the lumbar spine (L2–L4) and femoral neck (FN) using dual X-ray absortiometry (DEXA) in the first month after transplantation (baseline) and at 1, 2, and 3 years. At baseline, BMD was similar to the control population both in L2–L4 (z score ⫽ ⫺0.421) and in FN (z score ⫽ ⫺0.518). During the follow-up, 3 types of patterns were identified: BMD increased in L2–L4 in 25 patients (38.5%), remained stable in 20 patients (30.8%), and decreased in 20 patients (30.8%). BMD losses appeared mainly during the first year (0.964 ⫾ 0.162 baseline; 0.904 ⫾ 0.161 at 1 year, 0.886 ⫾ 0.140 at 3 years; analysis of variance [ANOVA] P ⬍ .001). However, the improvement was maintained throughout the follow-up (0.860 ⫾ 0.176 g/cm2 at baseline; 0.901 ⫾ 0.161 at 1 year; 0.954 ⫾ 0.178 at 3 years; ANOVA P ⬍ .001) and there was a parallel increase of BMD in FN (0.712 ⫾ 0.144 at baseline; 0.744 ⫾ 0.249 at 1 year; 0.826 ⫾ 0.184 at 3 years; ANOVA P ⬍ .01). There were no differences between both groups in graft function, intact parathyroid hormone (iPTH) levels, number of postmenopausal women, or steroid doses. About one third of patients had bone loss during the first year after transplantation. We were unable to identify any risk factor for this complication in patients on low-dose steroids
O
STEOPENIA expressed by low bone mineral density (BMD) is a frequent complication after kidney transplantation and appears early after the procedure.1 The evolution is variable; some investigators have observed that the bone loss is not progressive and that the bone density returned to basal values,2 but others have noted a persistently high rate of vertebral loss for many years after transplantation.3 The mechanisms responsible for this complication are unclear, but persistent hyperparathyroidism and immunosuppressive agents such as corticosteroids1,2,4 are among the possible risk factors. Despite the large amount of literature dealing with this issue in recent years, most of the data available come from cross-sectional studies or studies with a short-term follow-up. The purpose of the present study was to investigate prospectively the evolution of lumbar BMD in a population of renal transplant recipients on low-dose steroids during 3 years of follow-up.
PATIENTS AND METHODS A total of 65 patients with a functioning graft and with a follow-up of at least 3 years were included in the study. There were 41 men and 24 women, with a mean age at the time of transplantation of 47.1 ⫾ 13.5 years (range, 19 – 67 years); 14 patients were on treatment with cyclosporine and steroids (CsA) and 51 were on tacrolimus and steroids. After transplantation, the dose of prednisone was 250 mg the first day, 125 mg the second day, and 20 to 30 mg/d during the next 14 days; it was then gradually tapered to 5 mg/d. The initial dose of CsA was 8 mg/kg/d, adjusted thereafter to From the Departments of Nephrology (R.M., C.G., J.P., J.Oc., M.T., R.E., G.T., J.J.V., J.Or.), Nuclear Medicine (C.C.), and Urology (F.J.B.), Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain. Address reprint requests to Roberto Marcén, MD, Servicio de Nefrologı´a, Hospital Ramón y Cajal, Ctra Colmenar Viejo km 9.1, 28034 Madrid, Spain. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.02.034
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1466
Transplantation Proceedings, 37, 1466 –1467 (2005)
LUMBAR BONE MINERAL DENSITY maintain C0 blood levels between 150 –250 ng/mL. The initial dose of tacrolimus was 0.3 mg/kg/d, later adjusted to maintain blood levels between 10 and 20 ng/mL during the first 3 months and 5–15 ng/mL from then on. Renal function and serum biochemical markers of bone metabolism (calcium, phosphate, alkaline phosphatase, tubular reabsorption of phosphate, intact parathyroid hormone, 25(OH)-vitamin D3, and 1,25-(OH)2-vitamin D3) were prospectively determined at regular intervals during the follow-up. Measurements of BMD were done using dual X-ray absortiometry (DEXA) at the lumbar vertebral bodies L2–L4 and in the femoral neck (FN). BMD was evaluated on at least 4 examinations: at baseline and annually for 3 years. The same Lunar DPX scanner was used during the entire study. The results are expressed as mean ⫾ SD. Analysis of variance (ANOVA), paired and unpaired t tests, and chi-square tests were performed to assess the significance of differences between groups for continuous and categorical variables. P ⬍ .05 was considered significant.
RESULTS
At the time of transplantation, BMD in L2–L4 was 0.928 ⫾ 0.169 g/cm2 (z score ⫽ ⫺0.421 ⫾ 1.276) and in the FN 0.744 ⫾ 0.139 g/cm2. Serum parathyroid hormone (PTH) was 133 ⫾ 131 pg/mL and only 6 patients had levels ⬎250 ng/mL. After 3 years, BMD in L2–L4 was 0.930 ⫾ 0.161 g/cm2 in the entire group, similar to the baseline levels. When patients were classified according to the variation in BMD above ⫹2% (increase) and below ⫺2% (decrease) of the baseline values, BMD in L2–L4 increased in 25 patients (38.5%), decreased in 20 patients (30.6%), and remained unchanged in 20 patients (30.8%). In the group of patients in whom BMD decreased (⫺7.45%), bone loss mostly took place in the first year after transplantation and remained almost stable thereafter until the third year (0.964 ⫾ 0.162 baseline; 0.904 ⫾ 0.161 at 1 year; 0.900 ⫾ 0.148 at 2 years; 0.886 ⫾ 0.140 at 3 years; ANOVA P ⬍ .001). In the group of patients in whom BMD increased (⫹11.7%), the improvement was maintained throughout the study period (0.860 ⫾ 0.176 g/cm2 at baseline; 0.901 ⫾ 0.161 at 1 year; 0.923 ⫾ 0.174 at 2 years; 0.954 ⫾ 0.178 at 3 years; ANOVA P ⬍ .001). The increase of BMD in L2–L4 was accompanied by a parallel increase in BMD in FN (0.712 ⫾ 0.144 at baseline; 0.744 ⫾ 0.249 at 1 year; 0.763 ⫾ 0.214 at 2 years; 0.826 ⫾ 0.184 at 3 years; ANOVA P ⬍ .01). There were no differences between the groups in age, gender distribution, number of postmenopausal women, body mass index, PTH levels at baseline and at 1 year, corticosteroid doses and immunosuppression with CsA or tacrolimus, and graft function. The only difference we found was a lower BMD in L2–L4 in the group with decreased BMD at baseline (0.962 ⫾ 0.162 vs 0.850 ⫾ 0.176 g/cm2; P ⫽ .050). No fractures were observed during the follow-up. DISCUSSION
Our study showed that the evolution of BMD in L2–L4 after kidney transplantation is variable. In the majority of our patients, BMD increased or remained stable throughout the 3-year follow-up but BMD decreased significantly in nearly one third of the patients. These results are difficult to
1467
compare with previous studies because longitudinal studies with a 3-year follow-up are scarce. Moreno et al2 observed BMD loss in all 102 patients in the first 6 months after transplantation and a progressive recovery at 60 months, but they did not describe different BMD evolution patterns. Our results agree with those from Casez et al5 who also observed 3 patterns of BMD but the follow-up of their patients was only 18 months and the long-term evolution of BMD in the groups with bone loss and with bone gain is unknown. There are some other studies with follow-up for 3 years but the first evaluation of BMD was performed at least 12 months after transplantation. In 1 of these,6 BMD remained stable for the whole group of patients, but there was a subgroup with continuous bone loss during the 24 months of follow-up. Although several factors have been related to posttransplantation osteopenia, such as corticoids and hyperparathyroidism,2,4,5 we were unable to identify any risk factor in our study. The lack of relation between corticosteroid dose and bone loss in our patients could be explained in part by the low dose of prednisone administered, about 5 mg/d at 12 months, lower than the 7.5 mg proposed as the osteoporotic threshold dosage.1 The role of PTH in bone loss is debatable. In some studies, hyperparathyroidism was associated with bone loss in the first months after transplantation,2,4 but other studies found no relation between either high intact parathyroid hormone (iPTH) levels and bone loss or iPTH and biochemical markers of bone resorption.7 Finally, a continuous mineral loss has been described in those patients with lower PTH levels.5 In conclusion, the evolution of BMD after transplantation was variable. Bone loss occurred in about one third of patients, mostly during the first year after transplantation. However, bone density gain was maintained throughout the 3-year follow-up in nearly 40% of patients. The factors that determine the type of pattern could not be identified in this study. REFERENCES 1. Grotz WH, Mundinger FA, Gugel B, et al: Bone mineral density after renal transplantation. Transplantation 59:982, 1995 2. Moreno A, Torregrosa JV, Pons F, et al: Bone mineral density after renal transplantation: long-term follow-up. Transplant Proc 31:2322, 1999 3. Pichette V, Bonnardeaux L, Prudhomme L, et al: Long-term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study. Am J Kidney Dis 28:105, 1997 4. Torres A, Machado M, Concepción MT, et al: Influence of vitamin D receptor genotype on bone mass changes after renal transplantation. Kidney Int 50:1726, 1996 5. Casez J-P, Lippuner K, Horber FF, et al: Changes in bone mineral density over 18 months following kidney transplantation: the respective roles of prednisone and parathyroid hormone. Nephrol Dial Transplant 17:1318, 2002 6. Branderburg VM, Ketteler M, Fassbender WJ, et al: Development of lumbar bone mineral density in the late course after kidney transplantation. Am J Kidney Dis 40:1066, 2002 7. Cayco AV, Wysolmerski J, Simpson C, et al: Posttransplant bone disease: evidence for a high bone resorption state. Transplantation 70:1722, 2000
O
STEOPENIA expressed by low bone mineral density (BMD) is a frequent complication after kidney transplantation and appears early after the procedure.1 The evolution is variable; some investigators have observed that the bone loss is not progressive and that the bone density returned to basal values,2 but others have noted a persistently high rate of vertebral loss for many years after transplantation.3 The mechanisms responsible for this complication are unclear, but persistent hyperparathyroidism and immunosuppressive agents such as corticosteroids1,2,4 are among the possible risk factors. Despite the large amount of literature dealing with this issue in recent years, most of the data available come from cross-sectional studies or studies with a short-term follow-up. The purpose of the present study was to investigate prospectively the evolution of lumbar BMD in a population of renal transplant recipients on low-dose steroids during 3 years of follow-up.
PATIENTS AND METHODS A total of 65 patients with a functioning graft and with a follow-up of at least 3 years were included in the study. There were 41 men and 24 women, with a mean age at the time of transplantation of 47.1 ⫾ 13.5 years (range, 19 – 67 years); 14 patients were on treatment with cyclosporine and steroids (CsA) and 51 were on tacrolimus and steroids. After transplantation, the dose of prednisone was 250 mg the first day, 125 mg the second day, and 20 to 30 mg/d during the next 14 days; it was then gradually tapered to 5 mg/d. The initial dose of CsA was 8 mg/kg/d, adjusted thereafter to From the Departments of Nephrology (R.M., C.G., J.P., J.Oc., M.T., R.E., G.T., J.J.V., J.Or.), Nuclear Medicine (C.C.), and Urology (F.J.B.), Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain. Address reprint requests to Roberto Marcén, MD, Servicio de Nefrologı´a, Hospital Ramón y Cajal, Ctra Colmenar Viejo km 9.1, 28034 Madrid, Spain. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.02.034
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1466
Transplantation Proceedings, 37, 1466 –1467 (2005)
LUMBAR BONE MINERAL DENSITY maintain C0 blood levels between 150 –250 ng/mL. The initial dose of tacrolimus was 0.3 mg/kg/d, later adjusted to maintain blood levels between 10 and 20 ng/mL during the first 3 months and 5–15 ng/mL from then on. Renal function and serum biochemical markers of bone metabolism (calcium, phosphate, alkaline phosphatase, tubular reabsorption of phosphate, intact parathyroid hormone, 25(OH)-vitamin D3, and 1,25-(OH)2-vitamin D3) were prospectively determined at regular intervals during the follow-up. Measurements of BMD were done using dual X-ray absortiometry (DEXA) at the lumbar vertebral bodies L2–L4 and in the femoral neck (FN). BMD was evaluated on at least 4 examinations: at baseline and annually for 3 years. The same Lunar DPX scanner was used during the entire study. The results are expressed as mean ⫾ SD. Analysis of variance (ANOVA), paired and unpaired t tests, and chi-square tests were performed to assess the significance of differences between groups for continuous and categorical variables. P ⬍ .05 was considered significant.
RESULTS
At the time of transplantation, BMD in L2–L4 was 0.928 ⫾ 0.169 g/cm2 (z score ⫽ ⫺0.421 ⫾ 1.276) and in the FN 0.744 ⫾ 0.139 g/cm2. Serum parathyroid hormone (PTH) was 133 ⫾ 131 pg/mL and only 6 patients had levels ⬎250 ng/mL. After 3 years, BMD in L2–L4 was 0.930 ⫾ 0.161 g/cm2 in the entire group, similar to the baseline levels. When patients were classified according to the variation in BMD above ⫹2% (increase) and below ⫺2% (decrease) of the baseline values, BMD in L2–L4 increased in 25 patients (38.5%), decreased in 20 patients (30.6%), and remained unchanged in 20 patients (30.8%). In the group of patients in whom BMD decreased (⫺7.45%), bone loss mostly took place in the first year after transplantation and remained almost stable thereafter until the third year (0.964 ⫾ 0.162 baseline; 0.904 ⫾ 0.161 at 1 year; 0.900 ⫾ 0.148 at 2 years; 0.886 ⫾ 0.140 at 3 years; ANOVA P ⬍ .001). In the group of patients in whom BMD increased (⫹11.7%), the improvement was maintained throughout the study period (0.860 ⫾ 0.176 g/cm2 at baseline; 0.901 ⫾ 0.161 at 1 year; 0.923 ⫾ 0.174 at 2 years; 0.954 ⫾ 0.178 at 3 years; ANOVA P ⬍ .001). The increase of BMD in L2–L4 was accompanied by a parallel increase in BMD in FN (0.712 ⫾ 0.144 at baseline; 0.744 ⫾ 0.249 at 1 year; 0.763 ⫾ 0.214 at 2 years; 0.826 ⫾ 0.184 at 3 years; ANOVA P ⬍ .01). There were no differences between the groups in age, gender distribution, number of postmenopausal women, body mass index, PTH levels at baseline and at 1 year, corticosteroid doses and immunosuppression with CsA or tacrolimus, and graft function. The only difference we found was a lower BMD in L2–L4 in the group with decreased BMD at baseline (0.962 ⫾ 0.162 vs 0.850 ⫾ 0.176 g/cm2; P ⫽ .050). No fractures were observed during the follow-up. DISCUSSION
Our study showed that the evolution of BMD in L2–L4 after kidney transplantation is variable. In the majority of our patients, BMD increased or remained stable throughout the 3-year follow-up but BMD decreased significantly in nearly one third of the patients. These results are difficult to
1467
compare with previous studies because longitudinal studies with a 3-year follow-up are scarce. Moreno et al2 observed BMD loss in all 102 patients in the first 6 months after transplantation and a progressive recovery at 60 months, but they did not describe different BMD evolution patterns. Our results agree with those from Casez et al5 who also observed 3 patterns of BMD but the follow-up of their patients was only 18 months and the long-term evolution of BMD in the groups with bone loss and with bone gain is unknown. There are some other studies with follow-up for 3 years but the first evaluation of BMD was performed at least 12 months after transplantation. In 1 of these,6 BMD remained stable for the whole group of patients, but there was a subgroup with continuous bone loss during the 24 months of follow-up. Although several factors have been related to posttransplantation osteopenia, such as corticoids and hyperparathyroidism,2,4,5 we were unable to identify any risk factor in our study. The lack of relation between corticosteroid dose and bone loss in our patients could be explained in part by the low dose of prednisone administered, about 5 mg/d at 12 months, lower than the 7.5 mg proposed as the osteoporotic threshold dosage.1 The role of PTH in bone loss is debatable. In some studies, hyperparathyroidism was associated with bone loss in the first months after transplantation,2,4 but other studies found no relation between either high intact parathyroid hormone (iPTH) levels and bone loss or iPTH and biochemical markers of bone resorption.7 Finally, a continuous mineral loss has been described in those patients with lower PTH levels.5 In conclusion, the evolution of BMD after transplantation was variable. Bone loss occurred in about one third of patients, mostly during the first year after transplantation. However, bone density gain was maintained throughout the 3-year follow-up in nearly 40% of patients. The factors that determine the type of pattern could not be identified in this study. REFERENCES 1. Grotz WH, Mundinger FA, Gugel B, et al: Bone mineral density after renal transplantation. Transplantation 59:982, 1995 2. Moreno A, Torregrosa JV, Pons F, et al: Bone mineral density after renal transplantation: long-term follow-up. Transplant Proc 31:2322, 1999 3. Pichette V, Bonnardeaux L, Prudhomme L, et al: Long-term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study. Am J Kidney Dis 28:105, 1997 4. Torres A, Machado M, Concepción MT, et al: Influence of vitamin D receptor genotype on bone mass changes after renal transplantation. Kidney Int 50:1726, 1996 5. Casez J-P, Lippuner K, Horber FF, et al: Changes in bone mineral density over 18 months following kidney transplantation: the respective roles of prednisone and parathyroid hormone. Nephrol Dial Transplant 17:1318, 2002 6. Branderburg VM, Ketteler M, Fassbender WJ, et al: Development of lumbar bone mineral density in the late course after kidney transplantation. Am J Kidney Dis 40:1066, 2002 7. Cayco AV, Wysolmerski J, Simpson C, et al: Posttransplant bone disease: evidence for a high bone resorption state. Transplantation 70:1722, 2000