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ORIGINAL ARTICLE
Year : 2007  |  Volume : 17  |  Issue : 2  |  Page : 61-65
 

Efficacy and safety of alendronate in the prevention of bone loss in renal transplant recipients


Jondi Shapour University of Medical Sciences, Ahwaz, Iran

Correspondence Address:
H Shahbazian
Department of Kidney Transplantation, Golestan Hospital, Ahwaz
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-4065.37022

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  Abstract 

Background: The rapid loss of bone mass density occurs immediately after transplantation; this contributes to an increased risk for osteoporosis and fractures. The prevention and management of bone loss after renal transplantation is not elucidated thus far. The purpose of this study was to investigate whether the initiation of alendronate therapy immediately after transplantation can prevent bone loss and also to assess its safety on graft function and serum cyclosporine level. Materials and Methods: We conducted our study on 50 patients and randomly divided them into two groups: alendronate treatment group ( n = 25) and placebo group ( n = 25). Bone mineral density (BMD) of lumbar and femoral neck was measured using dual-energy X-ray absorptiometry prior to transplantation and after 6 months. The graft function was assessed by measuring the serum creatinine level and the serum cyclosporine trough level, which was measured by radioimmunoassay every 2 months until the end of the study. Results: The BMD in patients treated with alendronate increased significantly both at the lumbar vertebrae and femoral neck, while it decreased in the placebo group. The changes in the serum cyclosporine levels were independent of alendronate or placebo within 6 months after transplant. The graft function was similar between the groups. Conculsion: Alendronate was effective as well as safe for prophylaxis of rapid bone loss after renal transplantation.


Keywords: Alendronate, bone density, bone diseases, metabolic, transplantation


How to cite this article:
Shahbazian H, Mowla K, Shahbazian H B, Peydayesh B, Ehsanpour A. Efficacy and safety of alendronate in the prevention of bone loss in renal transplant recipients. Indian J Nephrol 2007;17:61-5

How to cite this URL:
Shahbazian H, Mowla K, Shahbazian H B, Peydayesh B, Ehsanpour A. Efficacy and safety of alendronate in the prevention of bone loss in renal transplant recipients. Indian J Nephrol [serial online] 2007 [cited 2019 Nov 21];17:61-5. Available from: http://www.indianjnephrol.org/text.asp?2007/17/2/61/37022



  Introduction Top


Kidney transplantation is now highly successful, and the achievement of long-term survival following renal transplantation requires the prevention of its late complications, including bone disease. Renal transplantation is usually associated with early bone loss that subsequently increases the risk of osteoporosis and fractures. [1],[2],[3] Rapid loss of bone mass has been reported in 28-88% of graft recipients after renal transplantation. [4],[5],[6] Up to 40% of renal graft recipients have spontaneous osteoporotic pain and approximately 60% of the patients experience fractures at least once during the follow-up. [7] The fracture risk for patients after renal transplantation is four times that of the general population [8],[9] and may be up to 34-fold higher in female kidney transplant recipients. [10] Immunosuppressive drugs exert protean effects on bone metabolism, including the altering of bone mineralization and formation through their action on osteoblasts. There is considerable uncertainty regarding the best management of bone disease in transplant recipients. Bisphosphonate agents are increasingly being used and recommended for use in transplant recipients. A prospective, randomized, controlled clinical trial was designed to evaluate the efficacy and safety of alendronate on Bone mineral density (BMD), serum creatinine and cyclosporine levels in adult renal recipients.


  Materials and Methods Top


This prospective placebo-controlled, randomized trial assessed 50 patients who underwent live-donor renal transplantation at our institute. Inclusion criteria were the patients with end stage renal disease (ESRD) who aged more than 18 years. We excluded patients who presented with the following: impaired graft function (i.e., serum creatinine >2 mg/dl) two weeks after transplantation, presence of previous fragility fractures, presence of hypogonadism, previously treated with bisphosphonates or other antiresorptive drugs, BMD with a t -score -2.5, history of major upper gastrointestinal illness such as peptic ulcer, esophagitis or severe dyspepsia, and inability to return for regular follow-up during the study period. The subjects were recruited between February 2005 and March 2006, after obtaining an informed consent according to local Institutional Review Board and followed for 6 months from the date of entry into the study.

All patients received prednisolone, cyclosporine and mycophenolate mofetil as immunosuppressive therapy. Some patients also received daclizumab or basiliximab. Cyclosporine dosages were adjusted to maintain the whole blood trough level between 200 and 300 ng/ml during the first 2 months and thereafter between 100 and 150 ng/ml. The subjects were randomized to one of two groups. Twenty-five subjects in the treatment group received oral alendronate 10 mg daily within 2 weeks after transplantation and 25 subjects in placebo group received placebo. Both groups received calcium carbonate 1 g/day and calcitriol 0.25 g/day.

All patients underwent routine laboratory tests, including renal function tests, parathyroid hormone estimation, albumin and cyclosporine trough level, at the baseline and at 2-month intervals for 6 months. Creatinine clearance was estimated using Cockroft-Gault formula.

Within 2 weeks prior to transplantation, patients underwent a baseline BMD scan with dual-energy X-ray absorptiometry (DEXA) and a scanner (Lunar Prodigy, Lunar Radiation Corp, Madison, WI, USA), using the recommended standard procedures of the manufacturer for the posteroanterior lumbar spine at L2-L4 and for the proximal femur at the femoral neck. Follow-up scans were performed 6 months after the transplantation. The BMD values were given in g/cm 2 and the results for each patient were expressed as z -scores and t -scores. These results were compared with the values of the age- and gender-matched reference populations ( z -score) and with the values of gender-matched peak bone mass of a young control population ( t -score). The diagnostic bone-mass threshold for defining osteoporosis in individuals without fractures was set at a t -score <-2.5 and for osteopenia was set at a t -score <-1. [11]

All the clinical and laboratory side effects that occurred during the study were recorded and their causes were evaluated.

Statistical analysis

Either the two-tailed Student's t -test for paired data or the nonparametric Wilcoxon signed-rank test was used for assessing differences in the same group at different time points. The Student's t -test for unpaired data or the Mann-Whitney U test were used for finding the differences between the groups. The effect of the use of alendronate on the renal function was analyzed at 6 months with univariate linear regression. Multivariate linear regression analysis was used to determine if serum cyclosporine trough level and creatinine clearance at the sixth month were influenced by independent variables of alendronate use. A p-value <0.05 was considered to be statistically significant. The statistical program SPSS version 11 (SPSS, Chicago, IL, USA) was used to analyze the data.


  Results Top


Baseline characteristics were similar in both the treatment groups [Table - 1]. Fifty patients were studied: 25 subjects (10 women and 15 men) in the treatment group received alendronate and 25 control subjects (8 women and 17 men) received placebo. The main causes of end-stage renal disease were similar between groups ( p = 0.41). There were no episodes of acute rejection or delayed graft function in any of the patients before enrolling in the study. No fractures or deaths were registered in any group during the observation period. There were no significant differences in the main cumulative steroids and cyclosporine doses after 6 months of follow-up for both the groups ( p = 0.23 and p = 0.12, respectively). During the study period, the prednisolone doses were further reduced in both groups and this reduction was not statistically significant between both the groups ( p = 0.09).

The various metabolic parameters and serum creatinine in the two groups at the baseline and after 6 months are shown in [Table - 2].

The cumulative doses of prednisone and cyclosporine were similar in both groups. The daily doses of prednisone and cyclosporine and the cyclosporine trough levels did not significantly differ between the groups. The serum cyclosporine levels at the time of starting the administration of alendronate and placebo was 231.04 ng/ml 87.83 and 227.16 ng/ml 69.54, respectively. After 6 months, the serum cyclosporine level was 219.20 ng/ml 81.83 in the alendronate group and 218.56 ng/ml 67.8 in the placebo group. There was no statistically significant differences between and within groups ( p = 0.07 and p = 0.17, respectively). The requirement for cyclosporine dose adjustment according to the cyclosporine trough levels was similar between the treatment and placebo groups.

Dual-energy X-ray absorptiometry measurements were available from all the patients at the baseline and after 6 months. At the baseline, osteopenia was observed in the lumbar spine and the femoral neck of 38% and 34% of the patients, respectively. The BMD in the two groups at baseline and 6 months is shown in [Table - 3]. The mineral content of the lumbar spine (g/cm 2 ) and the z -score improved significantly in patients receiving alendronate (mean differences: 3.2%; 95% CI; 2.1-7.8%; p < 0.05). In contrast, in placebo-treated patients, the BMD of the lumbar spine significantly deteriorated (mean differences: 2.2%; 95% CI; 0.73-3.4%; p < 0.05) [Table - 3]. At the femoral neck, the same trend of improvement was also found in the treatment group as compared with the control group ( p < 0.01). The DEXA measurements of the femur revealed a significant decrease in the BMD of the femoral neck in the placebo group, but not in patients receiving alendronate. After 6 months of follow-up, BMD at the femoral neck increased by 5.4% in the treatment group (95% CI; 4.8-10.7%; p < 0.05), whereas it decreased by -4% in the control group (95% CI; 1-4.3%; p < 0.05). The differences within the group before and after therapy and between groups were statistically significant [Table - 3]. The BMD changes at the lumbar and femoral neck were not affected by other factors such as sex, age, BMI and cause of renal failure, particularly the presence of diabetes mellitus. Only the BMD change in the femoral neck in the male patients in the placebo group was not statistically significant after 6 months ( p = 0.25).

Twenty percent of patients in the treatment group and 8% of patients in the placebo group reported mild to moderate dyspepsia and heartburn ( p < 0.01); however, severe abdominal pain or gastrointestinal upset was not reported and all the patients administered drugs during 6 months. Documented esophagitis or intestinal perforation was not reported. No severe episodes of hypercalcemia were recorded in both the groups; however, four episodes of hypercalcemia (defined as serum calcium level greater than 10.4 mg/dl) were reported in three cases (all in the placebo group), which were managed by the dose reduction in calcium supplements.


  Discussion Top


Rapid bone loss is more evident in the first 6 months after renal transplantation. [4],[6] This has been attributed mainly to the immunosuppressive therapy and in particular to corticosteroids. [6],[12],[13],[14],[15] The treatment modalities include supplemental calcium, vitamin D and its metabolites, antiresorptive drugs and drugs that exhibit a direct effect on bone formation. However, the use of different methods of prevention has not been well defined. In many studies, the glucocorticoid-induced bone loss was found to be ameliorated by bisphosphonates, which inhibit bone resorption. [16],[17] Our results indicated that the BMDs of both the lumbar spine and femoral neck were improved by the prophylactic treatment of the patients undergoing kidney transplantation with alendronate for 6 months. These results are in agreement with many other studies that demonstrated the substantial prevention of bone loss after transplantation. [18],[19],[20],[21],[22] Kovac et al. used alendronate in renal recipients for the first time. [18] They showed the beneficial effects of alendronate in osteoporotic renal recipients. Nowacka-Cieciura et al. showed no change in both the BMDs and t -scores of both the lumbar spine and femoral neck after a 6-month treatment with either alendronate or risedronate. However, they reported that BMD of lumbar spine improved significantly after 12 months. [21] Alendronate has been used not only immediately after kidney transplantation but also in long-standing kidney recipients. [23],[24],[25],[26] Most of these studies showed that alendronate is effective in restoring the BMD in renal recipients.

Our results suggest that in renal transplant recipients, bone loss is sustained despite the administration of calcium and vitamin D, which is in contrast to other studies. [27],[28],[29],[30],[31],[32],[33]

The safety of bisphosphonates in the setting of renal transplantation was assessed in several trials such as our study. In addition, we assessed the interaction between alendronate and cyclosporine by using serum cyclosporine trough levels for the first time. We found that serum cyclosporine level does not change during the treatment with alendronate. The serum creatinine level was similar between the two groups, and alendronate had no deleterious effect on the graft function.

The major limitation of our study is the relatively small number of patients and the short duration of follow-up. In addition, we did not assess the efficacy of alendronate on the incidence of fragility fracture in our patients. However, we excluded patients with BMD-defined osteoporosis to investigate the prophylactic effects of alendronate on bone loss. In addition, an important point in our study is that we initiated the treatment as early as the first week after transplantation to exclude the very rapid loss soon after transplantation so that the initial rapid bone loss after transplantation did not superimpose itself on the effects of the preventive treatment.


  Conclusion Top


Alendronate is effective in the prevention of bone loss after kidney transplantation. It does not interact with cyclosporine and has no adverse effects on graft function. Alendronate seems to be effective and safe after kidney transplantation. Long-term studies are required to investigate these results.

 
  References Top

1.Pichette V, Bonnardeaux A, Prudhomme L, Gagne M, Cardinal J, Ouimet D. Long term bone loss in kidney transplant recipients: A cross-sectional and longitudinal study. Am J Kidney Dis 1996;28:105-14.  Back to cited text no. 1    
2.Grotz WH, Mundinger FA, Rasenack J, Speidel L, Olschewski M, Exner VM, et al. Bone loss after kidney transplantation: A longitudinal study in 115 graft recipients. Nephrol Dial Transplant 1995;10:2096-100.  Back to cited text no. 2    
3.Torres A, Lorenzo V, Salido E. Calcium metabolism and skeletal problems after transplantation. J Am Soc Nephrol 2002;13:551-8.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991;325:544-50.  Back to cited text no. 4  [PUBMED]  
5.Casez JP, Lippuner K, Horber FF, Montandon A, Jaeger P. Changes in bone mineral density over 18 months following kidney transplantation: The respective roles of prednisone and parathyroid hormone. Nephrol Dial Transplant 2002;17:1318-26.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Mikuls TR, Julian BA, Bartolucci A, Saag KG. Bone mineral density changes within six months of renal transplantation. Transplantation 2003;75:49-54.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Vautour LM, Melton LJ, Clarke BL, Achenbach SJ, Oberg AL, McCarthy JT. Long-term fracture risk following renal transplantation: A population-based study. Osteoporos Int 2004;15:160-7.  Back to cited text no. 7    
8.Veenstra DL, Best JH, Hornberger J, Sullivan SD, Hricik DE. Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis 1999;33:829-39.  Back to cited text no. 8  [PUBMED]  
9.Grotz W, Mundinger F, Gugel B, Exner V, Kirste G, Schollmeyer PJ. Bone fracture and osteodensitometry with dual energy X-ray absorptiometry in kidney transplant recipients. Transplantation 1994;58:912-5.  Back to cited text no. 9    
10.Ramsey-Goldman R, Dunn JE, Dunlop DD, Stuart FP, Abecassis MM, Kaufman DB, et al. Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res 1999;14:456-63.  Back to cited text no. 10  [PUBMED]  
11.Cunningham J, Sprague SM, Cannata-Andia J, Coco M, Cohen-Solal M, Fitzpatrick L, et al. Osteoporosis in chronic kidney disease. Am J Kidney Dis 2004;43:566-71.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Canalis E. Mechanisms of glucocorticoid action in bone. Curr Osteoporos Rep 2005;3:98-102.  Back to cited text no. 12  [PUBMED]  
13.Nowacka-Cieciura E, Durlik M, Cieciura T, Talalaj M, Kukula K, Lewandowska D, et al. Positive effect of steroid withdrawal on bone mineral density in renal allograft recipients. Transplant Proc 2001;33:1273-7.  Back to cited text no. 13    
14.Rojas E, Carlini RG, Clesca P, Arminio A, Suniaga O, De Elguezabal K, et al. The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling. Kidney Int 2003;63:1915-23.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Weisinger JR, Carlini RG, Rojas E, Bellorin-Font E. Bone disease after renal transplantation. Clin J Am Soc Nephrol 2006;1:1300-13.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Suetonia C, Palmer SC, McGregor DO. Evaluation and management of bone disease following renal transplantation. Curr Opin Organ Transplant 2006;11:407-12.  Back to cited text no. 16    
17.Westenfeld R, Brandenburg VM, Ketteler M. Bisphosphonates can improve bone mineral density in renal transplant recipients. Nat Clin Pract Nephrol 2006;2:676-7.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Kovac D, Lindic J, Kandus A, Bren AF. Prevention of bone loss with alendronate in kidney transplant recipients. Transplantation 2000;70:1542-43.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Torregrosa JV, Moreno A, Gutiιrrez A, Vidal S, Oppenheimer F. Alendronate for treatment of renal transplant patients with osteoporosis. Transplant Proc 2003;35:1393-5.  Back to cited text no. 19    
20.El-Agroudy AE, El-Husseini AA, El-Sayed M, Mohsen T, Ghoneim MA. A prospective randomized study for the prevention of postrenal transplantation bone loss. Kidney Int 2005;67:2039-45.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Nowacka-Cieciura E, Cieciura T, Baczkowska T, Kozinska-Przybyl O, Tronina O, et al. Bisphosphonates are effective prophylactic of early bone loss after renal transplantation. Transplant Proc 2006;38:165-7.  Back to cited text no. 21    
22.Kovac D, Kandus A, Benedik M, Lindic J. Bone mineral density and histomorphology in kidney transplant recipients treated with alendronate in the early post transplant period. Transplantation 2006;82:357.  Back to cited text no. 22    
23.Koc M, Tuglular S, Arikan H, Ozener C, Akoglu E. Alendronate increases bone mineral density in long-term renal transplant recipients. Transplant Proc 2002;34:2111-3.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Giannini S, D'Angelo A, Carraro G, Nobile M, Rigotti P, Bonfante L, et al. Alendronate prevents further bone loss in renal transplant recipients. J Bone Miner Res 2001;16:2111-7.  Back to cited text no. 24  [PUBMED]  
25.Jeffery JR, Leslie WD, Karpinski ME, Nickerson PW, Rush DN. Prevalence and treatment of decreased bone density in renal transplant recipients: A randomized prospective trial of calcitriol versus alendronate. Transplantation 2003;76:1498-502.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Toro J, Gentil MA, Garcia R, Perez-Valdivia MA, Garcia Avellano E, Algarra GR, et al. Alendronate in kidney transplant patients: A single-center experience. Transplant Proc 2005;37:1471-2.  Back to cited text no. 26    
27.de Nijs RN, Jacobs JW, Lems WF, Laan RF, Algra A, Huisman AM, et al. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med 2006;355:675-84.  Back to cited text no. 27  [PUBMED]  [FULLTEXT]
28.Sambrook PN, Kotowicz M, Nash P, Styles CB, Naganathan V, Henderson-Briffa KN, et al. Prevention and treatment of glucocorticoid-induced osteoporosis: A comparison of calcitriol, vitamin D plus calcium and alendronate plus calcium. J Bone Miner Res 2003;18:919-24.  Back to cited text no. 28  [PUBMED]  
29.Berczi C, Asztalos L, Kincses Z, Balogh A, Locsey L, Balαzs G, et al. Comparison of calcium and alfacalcidol supplement in the prevention of osteopenia after kidney transplantation. Osteoporos Int 2003;14:412-7.  Back to cited text no. 29    
30.De Sevaux RG, Hoitsma AJ, Corstens FH, Wetzels JF. Treatment with vitamin D and calcium reduces bone loss after renal transplantation: A randomized study. J Am Soc Nephrol 2002;13:1608-14.  Back to cited text no. 30    
31.Josephson MA, Schumm LP, Chiu MY, Marshall C, Thistlethwaite JR, Sprague SM. Calcium and calcitriol prophylaxis attenuates post transplant bone loss. Transplantation 2004;78:1233-6.  Back to cited text no. 31  [PUBMED]  [FULLTEXT]
32.Shane E, Addesso V, Namerow PB, McMahon DJ, Lo SH, Staron RB, et al . Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 2004;350:767-76.  Back to cited text no. 32  [PUBMED]  [FULLTEXT]
33.Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al . Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1966;348:1535-41.  Back to cited text no. 33    



 
 
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  [Table - 1], [Table - 2], [Table - 3]



 

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