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Alendronate for treatment of renal transplant patients with osteoporosis
Alendronate for Treatment of Renal Transplant Patients With Osteoporosis J.V. Torregrosa, A. Moreno, A. Gutierrez, S. Vidal, and F. Oppenheimer ABSTRACT Osteoporosis is a frequent complication after renal transplantation. Some workers have shown that bisphosphonates may be effective to prevent and treat corticosteroid-induced osteoporosis in these patients. In this study we report our experience with administration of the biphosphonate alendronate to treat renal transplanted patients with established osteoporosis. Material and Methods. Twelve to 24 months after transplantation (9 women, 5 men) 14 renal transplant patient were treated with alendronate and 12 patients (7 women, 5 men) were untreated. All patients displayed an iPTH ⬍240 pg/mL and a bone mineral density (BMD) t-score ⬍⫺2.5. All patients received cyclosporine and prednisone therapy. Biochemical measurements, BMD, and X-rays of the lumbar spine were measured during study. Patients in the treatment group received alendronate 10 mg/d (po) and vitamin D plus calcium (800 UI cholecalciferol and 2.5 g of CaCO3) per day while those in the control group only received vitamin D plus calcium, at the same dose. Results. There was no difference in mean age, weight, time after transplantation, or immunosuppression between the treatment and control groups. There were no significant differences in the biochemical parameters during the study period. Over the 1-year study period, patients receiving alendronate displayed a greater increase in BMD. Lumbar spine BMD increased 4.3 ⫾ 6.1% in the treatment group versus 0.55 ⫾ 5.30% in controls. Femoral neck BMD increased 10.3 ⫾ 11.9% and 2.2 ⫾ 5.7%, respectively, in the treatment and control groups. Patients receiving alendronate frequently experienced intestinal disconfort. Conclusions. The bisphosphonate alendronate is effective to treat renal transplant patients suffering from established osteporosis.
O
STEOPOROSIS is a serious adverse event associated with corticosteroid therapy,1 which is used in maintenance immunosuppression regimens after renal transplantation, A loss of trabecular bone is known to result from prednisone doses of ⱖ7.5 mg/d, amounts that are frequent in renal transplant patients. Using dual-energy X-ray absorptiometry, several studies have shown (7% to 10% rates of bone loss during the first year after renal transplantation2,3; thereafter, the rate of bone loss declined.4,5 Long-term steroid therapy results in osteopenia via two mechanisms: decreased bone formation and increased bone resorption. Bisphosphonates exert their therapeutic effect by inhibiting bone resorption, binding preferentially to bones with high turnover rates. The efficacy of several © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1393-1395 (2003)
bisphosphonates for the treatment of corticosteroid-induced osteoporosis has been demonstrated in the general population and in transplanted patients.6,7 The aim of our study was to prospectively evaluate the effectiveness of bisphosphonate alendronate for the treatment of established osteoporosis in a renal transplant population.
From the Renal Transplant Unit, and Nuclear Medicine Department, Hospital Clinic, Barcelona, Spain. Address reprint requests to Dr J.V. Torregrosa, Renal Transplant Unit, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00479-2 1393
1394
TORREGROSA, MORENO, GUTIERREZ ET AL Table 1. Biochemical Parameters Baseline
Calcium (mg/dL) Phosphorus (mg/dL) Alkaline phosphatase (UI/L) iPTH (pg/mL) Creatinine (mg/dL)
12 months
Control
Treatment
Control
Treatment
9.9 ⫾ 1.6 4.0 ⫾ 1.0 167.0 ⫾ 79.0 92.0 ⫾ 55.0 1.3 ⫾ 0.6
10.3 ⫾ 1.2 4.1 ⫾ 0.7 145.0 ⫾ 66.0 110.0 ⫾ 47.0 1.4 ⫾ 0.4
10.4 ⫾ 1.1 4.0 ⫾ 0.9 164.0 ⫾ 49.0 86.0 ⫾ 39.0 1.4 ⫾ 0.5
9.7 ⫾ 0.8 4.2 ⫾ 0.7 101.0 ⫾ 57.0 147.0 ⫾ 61.0 1.5 ⫾ 0.6
P ⫽ NS.
PATIENTS AND METHODS The study included patients at between 12 and 24 months after renal transplantation, who were 18 to 70 years old, with serum creatinine of ⬍2 mg/dL, iPTH of ⬍240 pg/mL, and BMD with a t score of ⬍⫺2.5. Patients affected by diabetes mellitus were excluded. All patients were receiving immunosuppressive therapy with cyclosporine, adjusted to blood levels, and prednisone (5 to 7.5 mg per 24 hours). Patient underwent parathyroidectomy, or relevant changes in immunosuppressive therapy (especially steroid doses), or treatment with another drug that could affect BMD, during the study period. Twenty-six patients were studied: 14 subjects (9 women and 5 men) in the treatment group receiving alendronate, and 12 control subjects (7 women and 5 men) not receiving alendronate. Biochemical measurements, including serum creatinine, calcium, phosphorus, alkaline phosphatase, and iPTH, were determined at baseline, and 3, 6, and 12 months. BMD and X-rays of the lumbar spine were performed at baseline and at 6 and 12 months. Patients in the treatment group (n ⫽ 14) received alendronate (10 mg per os per day) and vitamin D plus calcium replacement (800 IU/d cholecalciferol and 2500 mg/d CaCO3). Patients in the control group received only vitamin D plus calcium replacement at the same dose. Patients were instructed to take the alendronate on an empty stomach in the morning. Bone mineral density (BMD) of the lumbar spine (L2– 4) and proximal femur (neck, greater trochanter, Ward’s triangle, and total femur) were measured by dual-energy X-ray absorptiometry (Lunar Prodigy, Lunar Radiation Corp, Madison Wisc). BMD values were obtained from lumbar vertebrae L-2, L-3, and L-4 and the proximal femur and expressed as grams per square centimeter and as z score and t score. Statistical analyses were performed using a two-tailed Student’s t test for differences between BMD measurements, and the chisquare test for nonparametric data.
RESULTS
There were no differences between the groups (treated versus untreated) with respect to age (57 ⫾ 8 and 53 ⫾ 9 years, respectively), weight (67 ⫾ 11 kg and 69 ⫾ 14 kg, respectively), time after renal transplantation (19 ⫾ 3 and
18 ⫾ 4 months, respectively), and immunosuppression (CsA and prednisone in all cases). There were no statistically significant differences in biochemical parameters between the groups at either baseline or follow-up (Table 1). Although BMD between the treatment and control groups at baseline showed no statistically significant differences, improvements in BMD of the lumbar spine (LS) and of the femoral neck (FN) were statistically significant after 1 year of treatment (Table 2). The majority (80%) in the treatment group noted minimal abdominal discomfort after the ingestion of the medication. DISCUSSION
Bone loss in renal transplant recipients is due to a combination of increased bone resorption and decreased bone formation. Factors contributing to both of these processes are most evident in the early posttransplantation period, especially the first 6 months, particularly in relating to high-dose steroid therapy and to secondary hyperparathyroidism.3 Treatment with antiresorptive medications, such as bisphosphonates, targets multiple factors contributing to this process in the renal transplant population. Some investigators8 have reported increased fracture rates (as high as twofold) for every 1-SD reduction of lumbar spine BMD, suggesting that this metric is a reasonable predictor for the risk of fractures. The mechanism of action of bisphosphonates to inhibit bone resorption is via direct and indirect effects on osteoclasts. Osteoclast activity is directly inhibited and numbers are reduced. Osteoclast survival may be decreased by destruction or apoptosis following contact with bone containing bisphosphonate. Clinical evidence of the efficacy of bisphosphonates for the treatment or prevention of corticosteroid-induced osteoporosis is available in several patient populations, both transplanted and nontransplanted.6,9 –11 Our study demonstrated that alendronate significantly improves BMD in patients with established osteoporosis
Table 2. BMD t ScorePercent of Change Baseline Group
LS FN *P ⬍ .001.
6 months
12 months
Control
Treatment
Control
Treatment
Control
Treatment
⫺3.01 ⫾ 0.80 ⫺2.01 ⫾ 0.70
⫺3.2 ⫾ 0.6 ⫺2.3 ⫾ 0.7
⫺2.7 ⫾ 0.6 ⫺1.8 ⫾ 0.6*
⫺1.8 ⫾ 0.8* ⫺1.6 ⫾ 0.6
⫺2.5 ⫾ 0.8 ⫺1.6 ⫾ 0.7
⫺1.4 ⫾ 0.8* ⫺1.3 ⫾ 0.6*
ALENDRONATE TREATMENT
when initiated 12 to 24 months after transplantation. A similar finding was reported by Arlen et al7 using etidronate 10 months after transplantation. Our data showed a statistically significant mean improvement in BMD in the lumbar spine and femoral neck compared with the control group. In our experience, alendronate was not well tolerated the majority of patients showed digestive intolerance, similar to the adverse reaction found in the general population. In summary, bisphosphonate alendronate is effective for the treatment of renal transplant patients with established osteporosis. It does not produce negative effects on renal function. The only inconvenience to the therapy is the poor digestive tolerance, which may be ameliorated by the novel formulation of alendronate that is (only administered) in a weekly regimen. REFERENCES 1. Lukert BP, Raisz LG: Ann Intern Med 112:352, 1990
1395 2. Julian BA, Laskow DA, Dubovsky J, et al: N Engl J Med 325:544, 1991 3. Torregrosa JV, Campistol JM, Montesinos M, et al: Transplant Proc 27:2224, 1995 4. Pichette V, Bonnardeaux A, Prudhomme L, et al: Am J Kidney Dis 28:105, 1996 5. Moreno A, Torregrosa JV, Pons F, et al: Transplant Proc 31:2322, 1999 6. Adachi JD, Cranney A, Goldsmith CH, et al: J Rheumatol 21:1922, 1994 7. Arlen DJ, Lambert K, Ioannidis G, et al: Transplantation 71:669, 2001 8. Melton LJ, Atkinson EJ, O’Fallen WM, et al: J Bone Miner Res 8:1227, 1993 9. Adachi JD, Bensen WG, Brown J, et al: N Engl J Med 337:382, 1997 10. Fan LS, Almond MK, Ball E, et al: Kidney Int 57:684, 2000 11. Haas M, Leko-Mohr Z, Roschger P, et al: Kidney Int 63:1130, 2003
O
STEOPOROSIS is a serious adverse event associated with corticosteroid therapy,1 which is used in maintenance immunosuppression regimens after renal transplantation, A loss of trabecular bone is known to result from prednisone doses of ⱖ7.5 mg/d, amounts that are frequent in renal transplant patients. Using dual-energy X-ray absorptiometry, several studies have shown (7% to 10% rates of bone loss during the first year after renal transplantation2,3; thereafter, the rate of bone loss declined.4,5 Long-term steroid therapy results in osteopenia via two mechanisms: decreased bone formation and increased bone resorption. Bisphosphonates exert their therapeutic effect by inhibiting bone resorption, binding preferentially to bones with high turnover rates. The efficacy of several © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1393-1395 (2003)
bisphosphonates for the treatment of corticosteroid-induced osteoporosis has been demonstrated in the general population and in transplanted patients.6,7 The aim of our study was to prospectively evaluate the effectiveness of bisphosphonate alendronate for the treatment of established osteoporosis in a renal transplant population.
From the Renal Transplant Unit, and Nuclear Medicine Department, Hospital Clinic, Barcelona, Spain. Address reprint requests to Dr J.V. Torregrosa, Renal Transplant Unit, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00479-2 1393
1394
TORREGROSA, MORENO, GUTIERREZ ET AL Table 1. Biochemical Parameters Baseline
Calcium (mg/dL) Phosphorus (mg/dL) Alkaline phosphatase (UI/L) iPTH (pg/mL) Creatinine (mg/dL)
12 months
Control
Treatment
Control
Treatment
9.9 ⫾ 1.6 4.0 ⫾ 1.0 167.0 ⫾ 79.0 92.0 ⫾ 55.0 1.3 ⫾ 0.6
10.3 ⫾ 1.2 4.1 ⫾ 0.7 145.0 ⫾ 66.0 110.0 ⫾ 47.0 1.4 ⫾ 0.4
10.4 ⫾ 1.1 4.0 ⫾ 0.9 164.0 ⫾ 49.0 86.0 ⫾ 39.0 1.4 ⫾ 0.5
9.7 ⫾ 0.8 4.2 ⫾ 0.7 101.0 ⫾ 57.0 147.0 ⫾ 61.0 1.5 ⫾ 0.6
P ⫽ NS.
PATIENTS AND METHODS The study included patients at between 12 and 24 months after renal transplantation, who were 18 to 70 years old, with serum creatinine of ⬍2 mg/dL, iPTH of ⬍240 pg/mL, and BMD with a t score of ⬍⫺2.5. Patients affected by diabetes mellitus were excluded. All patients were receiving immunosuppressive therapy with cyclosporine, adjusted to blood levels, and prednisone (5 to 7.5 mg per 24 hours). Patient underwent parathyroidectomy, or relevant changes in immunosuppressive therapy (especially steroid doses), or treatment with another drug that could affect BMD, during the study period. Twenty-six patients were studied: 14 subjects (9 women and 5 men) in the treatment group receiving alendronate, and 12 control subjects (7 women and 5 men) not receiving alendronate. Biochemical measurements, including serum creatinine, calcium, phosphorus, alkaline phosphatase, and iPTH, were determined at baseline, and 3, 6, and 12 months. BMD and X-rays of the lumbar spine were performed at baseline and at 6 and 12 months. Patients in the treatment group (n ⫽ 14) received alendronate (10 mg per os per day) and vitamin D plus calcium replacement (800 IU/d cholecalciferol and 2500 mg/d CaCO3). Patients in the control group received only vitamin D plus calcium replacement at the same dose. Patients were instructed to take the alendronate on an empty stomach in the morning. Bone mineral density (BMD) of the lumbar spine (L2– 4) and proximal femur (neck, greater trochanter, Ward’s triangle, and total femur) were measured by dual-energy X-ray absorptiometry (Lunar Prodigy, Lunar Radiation Corp, Madison Wisc). BMD values were obtained from lumbar vertebrae L-2, L-3, and L-4 and the proximal femur and expressed as grams per square centimeter and as z score and t score. Statistical analyses were performed using a two-tailed Student’s t test for differences between BMD measurements, and the chisquare test for nonparametric data.
RESULTS
There were no differences between the groups (treated versus untreated) with respect to age (57 ⫾ 8 and 53 ⫾ 9 years, respectively), weight (67 ⫾ 11 kg and 69 ⫾ 14 kg, respectively), time after renal transplantation (19 ⫾ 3 and
18 ⫾ 4 months, respectively), and immunosuppression (CsA and prednisone in all cases). There were no statistically significant differences in biochemical parameters between the groups at either baseline or follow-up (Table 1). Although BMD between the treatment and control groups at baseline showed no statistically significant differences, improvements in BMD of the lumbar spine (LS) and of the femoral neck (FN) were statistically significant after 1 year of treatment (Table 2). The majority (80%) in the treatment group noted minimal abdominal discomfort after the ingestion of the medication. DISCUSSION
Bone loss in renal transplant recipients is due to a combination of increased bone resorption and decreased bone formation. Factors contributing to both of these processes are most evident in the early posttransplantation period, especially the first 6 months, particularly in relating to high-dose steroid therapy and to secondary hyperparathyroidism.3 Treatment with antiresorptive medications, such as bisphosphonates, targets multiple factors contributing to this process in the renal transplant population. Some investigators8 have reported increased fracture rates (as high as twofold) for every 1-SD reduction of lumbar spine BMD, suggesting that this metric is a reasonable predictor for the risk of fractures. The mechanism of action of bisphosphonates to inhibit bone resorption is via direct and indirect effects on osteoclasts. Osteoclast activity is directly inhibited and numbers are reduced. Osteoclast survival may be decreased by destruction or apoptosis following contact with bone containing bisphosphonate. Clinical evidence of the efficacy of bisphosphonates for the treatment or prevention of corticosteroid-induced osteoporosis is available in several patient populations, both transplanted and nontransplanted.6,9 –11 Our study demonstrated that alendronate significantly improves BMD in patients with established osteoporosis
Table 2. BMD t ScorePercent of Change Baseline Group
LS FN *P ⬍ .001.
6 months
12 months
Control
Treatment
Control
Treatment
Control
Treatment
⫺3.01 ⫾ 0.80 ⫺2.01 ⫾ 0.70
⫺3.2 ⫾ 0.6 ⫺2.3 ⫾ 0.7
⫺2.7 ⫾ 0.6 ⫺1.8 ⫾ 0.6*
⫺1.8 ⫾ 0.8* ⫺1.6 ⫾ 0.6
⫺2.5 ⫾ 0.8 ⫺1.6 ⫾ 0.7
⫺1.4 ⫾ 0.8* ⫺1.3 ⫾ 0.6*
ALENDRONATE TREATMENT
when initiated 12 to 24 months after transplantation. A similar finding was reported by Arlen et al7 using etidronate 10 months after transplantation. Our data showed a statistically significant mean improvement in BMD in the lumbar spine and femoral neck compared with the control group. In our experience, alendronate was not well tolerated the majority of patients showed digestive intolerance, similar to the adverse reaction found in the general population. In summary, bisphosphonate alendronate is effective for the treatment of renal transplant patients with established osteporosis. It does not produce negative effects on renal function. The only inconvenience to the therapy is the poor digestive tolerance, which may be ameliorated by the novel formulation of alendronate that is (only administered) in a weekly regimen. REFERENCES 1. Lukert BP, Raisz LG: Ann Intern Med 112:352, 1990
1395 2. Julian BA, Laskow DA, Dubovsky J, et al: N Engl J Med 325:544, 1991 3. Torregrosa JV, Campistol JM, Montesinos M, et al: Transplant Proc 27:2224, 1995 4. Pichette V, Bonnardeaux A, Prudhomme L, et al: Am J Kidney Dis 28:105, 1996 5. Moreno A, Torregrosa JV, Pons F, et al: Transplant Proc 31:2322, 1999 6. Adachi JD, Cranney A, Goldsmith CH, et al: J Rheumatol 21:1922, 1994 7. Arlen DJ, Lambert K, Ioannidis G, et al: Transplantation 71:669, 2001 8. Melton LJ, Atkinson EJ, O’Fallen WM, et al: J Bone Miner Res 8:1227, 1993 9. Adachi JD, Bensen WG, Brown J, et al: N Engl J Med 337:382, 1997 10. Fan LS, Almond MK, Ball E, et al: Kidney Int 57:684, 2000 11. Haas M, Leko-Mohr Z, Roschger P, et al: Kidney Int 63:1130, 2003