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Bone Disease after Kidney Transplantation

2006; Elsevier BV; Volume: 13; Issue: 1 Linguagem: Inglês

10.1053/j.ackd.2005.10.008

1548-5609

Anna L. Zisman, Stuart M. Sprague,

Heterotopic Ossification and Related Conditions

Advances in immunosuppressive therapy have allowed for enhanced allograft survival in kidney transplantation. With this increasing success of transplantation, however, has come a greater appreciation of subsequent complications, such as bone and mineral disease. In patients with chronic kidney disease who are awaiting transplantation, disorders in mineral metabolism and renal osteodystrophy are an essentially universal finding, and several different pathophysiologic mechanisms are believed to contribute to the development of these disorders. Advances in immunosuppressive therapy have allowed for enhanced allograft survival in kidney transplantation. With this increasing success of transplantation, however, has come a greater appreciation of subsequent complications, such as bone and mineral disease. In patients with chronic kidney disease who are awaiting transplantation, disorders in mineral metabolism and renal osteodystrophy are an essentially universal finding, and several different pathophysiologic mechanisms are believed to contribute to the development of these disorders. Secondary hyperparathyroidism that results from impaired calcium and phosphate balance coupled with vitamin D (calcitriol) deficiency ultimately leads to osteitis fibrosa cystica, a high bone-turnover lesion. The pathogenesis of low bone-turnover disease (osteomalacia, adynamic bone disease, and aluminum bone disease) is less clear but has been associated with diabetes mellitus, peritoneal dialysis, advancing age, and is felt to be, at least in part, caused by bone resistance to PTH. Osteoporosis, osteosclerosis, and β2-microglobulin amyloidosis are additional factors that affect bone health in this population. Furthermore, hypogonadism, metabolic acidosis and medications such as loop diuretics, heparin, glucocorticoids, antiepileptics, and calcineurin inhibitors have been implicated as contributors to pretransplantation bone disease. After successful transplantation, in the setting of the above underlying disorders, additional insults such as the effects of immunosuppressive medications, evolution of the underlying bone disease, persistent hyperparathyroidism, recurrence of kidney dysfunction, and the development of phosphaturia further complicate bone health in these patients. This combination of factors, which stems from the impairment of kidney function and disorders of mineral metabolism, leads to the development of fractures after transplantation. Patients with chronic kidney disease before transplantation are at increased risk for bone fractures. The prevalence of vertebral fracture is estimated to be approximately 1 in 5, and the relative risk of hip fracture is increased by at least 2-fold to 14-fold. Demographic risk factors for pretransplant fracture include advanced age, female gender, and Caucasian race.1Stehman-Breen C.O. Sherrard D.J. Alem A.M. et al.Risk factors for hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 2200-2205Crossref PubMed Google Scholar The duration of dialysis,2Alem A.M. Sherrard D.J. Gillen D.L. et al.Increased risk of hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 396-399Crossref PubMed Scopus (653) Google Scholar the presence of diabetic nephropathy,3Ball A.M. Gillen D.L. Sherrard D. et al.Risk of hip fracture among dialysis and renal transplant recipients.JAMA. 2002; 288: 3014-3018Crossref PubMed Scopus (349) Google Scholar positive history of peripheral vascular disease,1Stehman-Breen C.O. Sherrard D.J. Alem A.M. et al.Risk factors for hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 2200-2205Crossref PubMed Google Scholar low bone-mineral density (BMD), and lower PTH levels are clinical harbingers of fracture risk. After successful kidney transplantation, fracture rates between 5% and 45% have been reported.4Elmstedt E. Svahn T. Skeletal complications following renal transplantation.Acta Orthop Scand. 1981; 52: 279-286Crossref PubMed Scopus (45) Google Scholar, 5Davidson J.K. Tsakiris D. Briggs J.D. et al.Osteonecrosis and fractures following renal transplantation.Clin Radiol. 1985; 36: 27-35Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 6Ramsey-Goldman R.R. Dunn J.E. Dunlop D.D. et al.Increased risk of fracture in patients receiving solid organ transplants.J Bone Miner Res. 1999; 14: 456-463Crossref PubMed Scopus (218) Google Scholar, 7Arlen D.J. Lambert K. Ioannidis G. et al.Treatment of established bone loss after renal transplantation with etidronate.Transplantation. 2001; 71: 669-673Crossref PubMed Scopus (38) Google Scholar, 8O'Shaughnessy E.A. Dahl D.C. Smith C.L. et al.Risk factors for fractures in kidney transplantation.Transplantation. 2002; 74: 362-366Crossref PubMed Scopus (88) Google Scholar, 9Durieux S. Mercadal L. Orcel P. et al.Bone mineral density and fracture prevalence in long-term kidney graft recipients.Transplantation. 2002; 74: 496-500Crossref PubMed Scopus (112) Google Scholar, 10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar, 11Parker C.R. Freemont A.J. Blackwell P.J. et al.Cross-sectional analysis of renal transplantation osteoporosis.J Bone Miner Res. 1999; 14: 1943-1951Crossref PubMed Scopus (73) Google Scholar, 12Patel S. Kwan J.T.C. McCloskey E. et al.Prevalence and causes of low bone density and fractures in kidney transplant patients.J Bone Miner Res. 2001; 16: 1863-1870Crossref PubMed Scopus (87) Google Scholar, 13D'Angelo A. Calo L. Giannini S. et al.Parathyroid hormone and bone metabolism in kidney-transplanted patients.Clin Nephrol. 2000; 53: 19-22PubMed Google Scholar, 14Nam J.H. Moon J.I. Chung S.S. et al.Prevalence and risk factors for vertebral fractures in renal transplants.Transplant Proc. 2000; 32: 1877Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The rate variability seen among the studies results from a number of causes, including whether the fractures were self-reported via questionnaire or clinical documentation was required. An additional factor that likely contributes to the variation is the difference in the posttransplant timing among the reports. As depicted in Figure 1 (r = 0.7; P = .03), the reported fracture rate is positively correlated with time since transplantation.4Elmstedt E. Svahn T. Skeletal complications following renal transplantation.Acta Orthop Scand. 1981; 52: 279-286Crossref PubMed Scopus (45) Google Scholar, 5Davidson J.K. Tsakiris D. Briggs J.D. et al.Osteonecrosis and fractures following renal transplantation.Clin Radiol. 1985; 36: 27-35Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 6Ramsey-Goldman R.R. Dunn J.E. Dunlop D.D. et al.Increased risk of fracture in patients receiving solid organ transplants.J Bone Miner Res. 1999; 14: 456-463Crossref PubMed Scopus (218) Google Scholar, 7Arlen D.J. Lambert K. Ioannidis G. et al.Treatment of established bone loss after renal transplantation with etidronate.Transplantation. 2001; 71: 669-673Crossref PubMed Scopus (38) Google Scholar, 8O'Shaughnessy E.A. Dahl D.C. Smith C.L. et al.Risk factors for fractures in kidney transplantation.Transplantation. 2002; 74: 362-366Crossref PubMed Scopus (88) Google Scholar, 9Durieux S. Mercadal L. Orcel P. et al.Bone mineral density and fracture prevalence in long-term kidney graft recipients.Transplantation. 2002; 74: 496-500Crossref PubMed Scopus (112) Google Scholar, 10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar, 11Parker C.R. Freemont A.J. Blackwell P.J. et al.Cross-sectional analysis of renal transplantation osteoporosis.J Bone Miner Res. 1999; 14: 1943-1951Crossref PubMed Scopus (73) Google Scholar, 12Patel S. Kwan J.T.C. McCloskey E. et al.Prevalence and causes of low bone density and fractures in kidney transplant patients.J Bone Miner Res. 2001; 16: 1863-1870Crossref PubMed Scopus (87) Google Scholar, 13D'Angelo A. Calo L. Giannini S. et al.Parathyroid hormone and bone metabolism in kidney-transplanted patients.Clin Nephrol. 2000; 53: 19-22PubMed Google Scholar, 14Nam J.H. Moon J.I. Chung S.S. et al.Prevalence and risk factors for vertebral fractures in renal transplants.Transplant Proc. 2000; 32: 1877Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The proportion of patients with diabetes mellitus also varied among reports, which may skew estimates because patients who received a kidney-pancreas transplant have reported fracture rates as high as 40% and 49% after transplantation.15Chiu M.Y. Sprague S.M. Bruce D.S. et al.Analysis of fracture prevalence in kidney-pancreas allograft recipients.J Am Soc Nephrol. 1998; 9: 677-683PubMed Google Scholar, 16Nisbeth U. Lindh E. Ljunghall S. et al.Increased fracture rate in diabetes mellitus and females after renal transplantation.Transplantation. 1999; 67: 1218-1222Crossref PubMed Scopus (115) Google Scholar Overall, the fracture risk is significantly higher for kidney-transplant and kidney-pancreas–transplant recipients than for the general population.6Ramsey-Goldman R.R. Dunn J.E. Dunlop D.D. et al.Increased risk of fracture in patients receiving solid organ transplants.J Bone Miner Res. 1999; 14: 456-463Crossref PubMed Scopus (218) Google Scholar The transplant recipient's increased fracture risk is confirmed by the increased incidence of hospitalization for fracture. In one report, for example, Abbott et al17Abbott K.C. Oglesby R.J. Hypolite I.O. et al.Hospitalizations for fractures after renal transplantation in the United States.Epidemiology. 2001; 11: 450-457Abstract Full Text Full Text PDF Scopus (110) Google Scholar found that in 33,479 transplant recipients 3 years or less after transplantation, the relative risk of being hospitalized for a fracture was 4.59 compared with the general population. Risk factors for posttransplant fracture are similar to those for fracture before transplantation and include duration of hemodialysis before transplant,12Patel S. Kwan J.T.C. McCloskey E. et al.Prevalence and causes of low bone density and fractures in kidney transplant patients.J Bone Miner Res. 2001; 16: 1863-1870Crossref PubMed Scopus (87) Google Scholar time since transplant,12Patel S. Kwan J.T.C. McCloskey E. et al.Prevalence and causes of low bone density and fractures in kidney transplant patients.J Bone Miner Res. 2001; 16: 1863-1870Crossref PubMed Scopus (87) Google Scholar female gender (especially if postmenopausal),10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar, 12Patel S. Kwan J.T.C. McCloskey E. et al.Prevalence and causes of low bone density and fractures in kidney transplant patients.J Bone Miner Res. 2001; 16: 1863-1870Crossref PubMed Scopus (87) Google Scholar decreased BMD,10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar kidney failure secondary to diabetes,10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar previous fracture before transplantation,10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar and age older than 45 years.4Elmstedt E. Svahn T. Skeletal complications following renal transplantation.Acta Orthop Scand. 1981; 52: 279-286Crossref PubMed Scopus (45) Google Scholar Obesity, in contrast, was associated with a reduced risk of fracture.10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar However, although a low BMD increases a recipient's fracture risk, many patients with low BMD never fracture; thus, BMDs do not provide the means to determine who will or will not experience a fracture.10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar Although posttransplant fractures can occur both peripherally (wrists, fingers, ankles, or feet) and centrally (ribs, hip, or vertebrae), multiple studies have suggested a higher fracture rate at peripheral sites (Fig 2).4Elmstedt E. Svahn T. Skeletal complications following renal transplantation.Acta Orthop Scand. 1981; 52: 279-286Crossref PubMed Scopus (45) Google Scholar, 7Arlen D.J. Lambert K. Ioannidis G. et al.Treatment of established bone loss after renal transplantation with etidronate.Transplantation. 2001; 71: 669-673Crossref PubMed Scopus (38) Google Scholar, 8O'Shaughnessy E.A. Dahl D.C. Smith C.L. et al.Risk factors for fractures in kidney transplantation.Transplantation. 2002; 74: 362-366Crossref PubMed Scopus (88) Google Scholar, 9Durieux S. Mercadal L. Orcel P. et al.Bone mineral density and fracture prevalence in long-term kidney graft recipients.Transplantation. 2002; 74: 496-500Crossref PubMed Scopus (112) Google Scholar, 10Grotz W.H. Mundinger F.A. Gugel B. et al.Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients.Transplantation. 1994; 58: 912-915Crossref PubMed Scopus (199) Google Scholar, 16Nisbeth U. Lindh E. Ljunghall S. et al.Increased fracture rate in diabetes mellitus and females after renal transplantation.Transplantation. 1999; 67: 1218-1222Crossref PubMed Scopus (115) Google Scholar In addition to the globally increased risk of posttransplant fracture, patients with diabetes mellitus are particularly at risk for peripheral fractures.15Chiu M.Y. Sprague S.M. Bruce D.S. et al.Analysis of fracture prevalence in kidney-pancreas allograft recipients.J Am Soc Nephrol. 1998; 9: 677-683PubMed Google Scholar, 16Nisbeth U. Lindh E. Ljunghall S. et al.Increased fracture rate in diabetes mellitus and females after renal transplantation.Transplantation. 1999; 67: 1218-1222Crossref PubMed Scopus (115) Google Scholar Low BMD at the spine, hip, and distal radius is pervasive in patients with chronic kidney disease. Female gender and Caucasian race are two of the demographic factors associated with low BMD, and clinical risk factors for low BMD include prolonged duration of hemodialysis, amenorrhea, elevated PTH, lower weight or body mass index (BMI), and previous kidney transplantation. After transplantation, recipients of either kidney transplants or combined kidney-pancreas transplants have been shown in numerous reports to rapidly lose bone.18Kwan J.T. Almond M.K. Evans K. et al.Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation.Miner Electrolyte Metab. 1992; 18: 166-168PubMed Google Scholar, 19Feber J. Cochat P. Braillon P. et al.Bone mineral density after renal transplantation in children.J Pediatr. 1994; 6: 870-875Abstract Full Text Full Text PDF Scopus (68) Google Scholar, 20McIntyre H.D. Menzies B. Rigby R. et al.Long-term bone loss after renal transplantation Comparison of immunosuppressive regimens.Clin Transplant. 1995; 9: 20-24PubMed Google Scholar, 21Torres A. Machado M. Concepcion M.T. et al.Influence of vitamin D receptor genotype on bone mass changes after renal transplantation.Kidney Int. 1996; 50: 1726-1733Crossref PubMed Scopus (87) Google Scholar, 22Yun Y.S. Kim B.J. Hong S.P. et al.Changes of bone metabolism indices in patients receiving immunosuppressive therapy including low doses of steroids after renal transplantation.Transplant Proc. 1996; 28: 1561-1564PubMed Google Scholar, 23Kim M.S. Kim Y.S. Lim S.K. et al.Effect of deflazacort on bone mineral density in renal transplant recipients.Transplant Proc. 1998; 30: 3041-3042Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 24Lippuner K. Casez J.-P. Horber F.F. et al.Effects of deflazacort versus prednisone on bone mass, body composition and lipid profile A randomized double blind study in kidney transplant patients.J Clin Endocrinol Metab. 1998; 83: 3795-3802Crossref PubMed Scopus (66) Google Scholar, 25Smets Y.F.C. van der Pijl J.W. Ringers J. et al.Pattern of bone loss after simultaneous pancreas-kidney transplantation A prospective study.Transplant Proc. 1998; 30: 326Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 26Isiklar I. Akin O. Demirag A. et al.Changes in bone mineral density after renal transplantation.Transplant Proc. 1998; 30 (814–185)Google Scholar, 27Moreno A. Torregrosa J.V. Pons F. et al.Bone mineral density after renal transplantation.Transplant Proc. 1999; 31: 2322-2323Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 28Fan S.L.S. Almond M.K. Ball E. et al.Pamidronate therapy as prevention of bone loss following renal transplantation.Kidney Int. 2000; 57: 684-690PubMed Google Scholar, 29Nam J.-H. Moon J.I. Chung S.-S. et al.Pamidronate and calcitriol trial for the prevention of early bone loss after renal transplantation.Transplant Proc. 2000; 32: 1876Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 30Kokado Y. Takahara S. Ichimaru N. et al.Factors influencing vertebral bone density after renal transplantation.Transpl Int. 2000; 13: S431-S435Crossref PubMed Google Scholar, 31Goffin E. Devogelaer J.-P. Lalaoui A. et al.Tacrolimus and low-dose steroid immunosuppression preserves bone mass after renal transplantation.Transpl Int. 2002; 15: 73-80Crossref PubMed Scopus (56) Google Scholar, 32Julian B.A. Laskow D.A. Dubovsky J. et al.Rapid loss of vertebral mineral density after renal transplantation.N Engl J Med. 1991; 325: 544-550Crossref PubMed Scopus (605) Google Scholar, 33Horber F.F. Casez J.P. Steiger U. et al.Changes in bone mass early after kidney transplantation.J Bone Miner Res. 1994; 9: 1-9Crossref PubMed Scopus (204) Google Scholar, 34Almond M.K. Kwan J.T. Evans K. et al.Loss of regional bone mineral density in the first 12 months following renal transplantation.Nephron. 1994; 66: 52-57Crossref PubMed Scopus (190) Google Scholar, 35Grotz W. Nagel C. Poeschel D. et al.Effect of ibandronate on bone loss and renal function after kidney transplantation.J Am Soc Nephrol. 2001; 12: 1530-1537PubMed Google Scholar, 36Grotz W.H. Mundinger F.A. Gugel B. et al.Bone mineral density after kidney transplantation. A cross-sectional study in 190 graft recipients up to 20 years after transplantation.Transplantation. 1995; 59: 982-986Crossref PubMed Scopus (148) Google Scholar When measured by dual X-ray absorptiometry (DEXA) scans, significant losses of BMD have been detected as early as 3 months after transplantation. At the 3-month juncture, Almond et al34Almond M.K. Kwan J.T. Evans K. et al.Loss of regional bone mineral density in the first 12 months following renal transplantation.Nephron. 1994; 66: 52-57Crossref PubMed Scopus (190) Google Scholar noted a 3.93% decline in femoral neck BMD in male transplant recipients. At 6 months, Julian et al32Julian B.A. Laskow D.A. Dubovsky J. et al.Rapid loss of vertebral mineral density after renal transplantation.N Engl J Med. 1991; 325: 544-550Crossref PubMed Scopus (605) Google Scholar found a deterioration of 6.8% in lumbar spine BMD. Both trabecular bone and cortical bone appear to be involved, as significant decreases in BMDs at the lumbar spine (mostly trabecular) and at the femoral neck (mostly cortical) have been documented.18Kwan J.T. Almond M.K. Evans K. et al.Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation.Miner Electrolyte Metab. 1992; 18: 166-168PubMed Google Scholar, 25Smets Y.F.C. van der Pijl J.W. Ringers J. et al.Pattern of bone loss after simultaneous pancreas-kidney transplantation A prospective study.Transplant Proc. 1998; 30: 326Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 27Moreno A. Torregrosa J.V. Pons F. et al.Bone mineral density after renal transplantation.Transplant Proc. 1999; 31: 2322-2323Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 28Fan S.L.S. Almond M.K. Ball E. et al.Pamidronate therapy as prevention of bone loss following renal transplantation.Kidney Int. 2000; 57: 684-690PubMed Google Scholar, 33Horber F.F. Casez J.P. Steiger U. et al.Changes in bone mass early after kidney transplantation.J Bone Miner Res. 1994; 9: 1-9Crossref PubMed Scopus (204) Google Scholar, 34Almond M.K. Kwan J.T. Evans K. et al.Loss of regional bone mineral density in the first 12 months following renal transplantation.Nephron. 1994; 66: 52-57Crossref PubMed Scopus (190) Google Scholar, 35Grotz W. Nagel C. Poeschel D. et al.Effect of ibandronate on bone loss and renal function after kidney transplantation.J Am Soc Nephrol. 2001; 12: 1530-1537PubMed Google Scholar, 36Grotz W.H. Mundinger F.A. Gugel B. et al.Bone mineral density after kidney transplantation. A cross-sectional study in 190 graft recipients up to 20 years after transplantation.Transplantation. 1995; 59: 982-986Crossref PubMed Scopus (148) Google Scholar Some authors have reported stable BMDs after transplantation, which has been attributed to variable effects of different immunosuppressive regimens. Deflazacort-treated patients suffered less bone loss than patients treated with prednisone,23Kim M.S. Kim Y.S. Lim S.K. et al.Effect of deflazacort on bone mineral density in renal transplant recipients.Transplant Proc. 1998; 30: 3041-3042Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 24Lippuner K. Casez J.-P. Horber F.F. et al.Effects of deflazacort versus prednisone on bone mass, body composition and lipid profile A randomized double blind study in kidney transplant patients.J Clin Endocrinol Metab. 1998; 83: 3795-3802Crossref PubMed Scopus (66) Google Scholar and cyclosporine appeared to confer a benefit compared with azathioprine.20McIntyre H.D. Menzies B. Rigby R. et al.Long-term bone loss after renal transplantation Comparison of immunosuppressive regimens.Clin Transplant. 1995; 9: 20-24PubMed Google Scholar Furthermore, in contrast to cyclosporine-treated patients who lost bone, tacrolimus-treated patients experienced bone gain.31Goffin E. Devogelaer J.-P. Lalaoui A. et al.Tacrolimus and low-dose steroid immunosuppression preserves bone mass after renal transplantation.Transpl Int. 2002; 15: 73-80Crossref PubMed Scopus (56) Google Scholar The influence of the vitamin D receptor genotype bb is controversial but may also be advantageous in the prevention of posttransplant bone loss.21Torres A. Machado M. Concepcion M.T. et al.Influence of vitamin D receptor genotype on bone mass changes after renal transplantation.Kidney Int. 1996; 50: 1726-1733Crossref PubMed Scopus (87) Google Scholar Although a number of risk factors for posttransplant bone loss have been determined, a discordance exists among studies as to which factors confer risk. The currently identified risk factors include mounting total glucocorticoid exposure,12Patel S. Kwan J.T.C. McCloskey E. et al.Prevalence and causes of low bone density and fractures in kidney transplant patients.J Bone Miner Res. 2001; 16: 1863-1870Crossref PubMed Scopus (87) Google Scholar, 20McIntyre H.D. Menzies B. Rigby R. et al.Long-term bone loss after renal transplantation Comparison of immunosuppressive regimens.Clin Transplant. 1995; 9: 20-24PubMed Google Scholar, 22Yun Y.S. Kim B.J. Hong S.P. et al.Changes of bone metabolism indices in patients receiving immunosuppressive therapy including low doses of steroids after renal transplantation.Transplant Proc. 1996; 28: 1561-1564PubMed Google Scholar, 37Ugur A. Guvener N. Isiklar I. et al.Osteoporosis after renal transplantation Single center experience.Transplantation. 2001; 71: 645-649Crossref PubMed Scopus (32) Google Scholar, 38Nowacka-Cieciura E. Durlik M. Cieciura T. et al.Steroid withdrawal after renal transplantation-risks and benefits.Transplant Proc. 2002; 34: 560-563Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar prolonged duration of dialysis before transplantation,39Aroldi A. Tarantino A. Montagnino G. et al.Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients A prospective study.Transplantation. 1997; 63: 380-386Crossref PubMed Scopus (141) Google Scholar and increasing time since transplantation.12Patel S. Kwan J.T.C. McCloskey E. et al.Prevalence and causes of low bone density and fractures in kidney transplant patients.J Bone Miner Res. 2001; 16: 1863-1870Crossref PubMed Scopus (87) Google Scholar, 37Ugur A. Guvener N. Isiklar I. et al.Osteoporosis after renal transplantation Single center experience.Transplantation. 2001; 71: 645-649Crossref PubMed Scopus (32) Google Scholar, 40Bagni B. Gilli P. Cavallini A. et al.Continuing loss of vertebral mineral density in renal transplant recipients.Eur J Nucl Med. 1994; 21: 108-112Crossref PubMed Scopus (37) Google Scholar With regard to the role of increasing time since transplantation, 12 studies of transplant recipients several years after transplantation have been conducted. Of these studies, three did not reveal a significant drop,22Yun Y.S. Kim B.J. Hong S.P. et al.Changes of bone metabolism indices in patients receiving immunosuppressive therapy including low doses of steroids after renal transplantation.Transplant Proc. 1996; 28: 1561-1564PubMed Google Scholar, 36Grotz W.H. Mundinger F.A. Gugel B. et al.Bone mineral density after kidney transplantation. A cross-sectional study in 190 graft recipients up to 20 years after transplantation.Transplantation. 1995; 59: 982-986Crossref PubMed Scopus (148) Google Scholar, 41Hurst G. Alloway R. Hathaway D. et al.Stabilization of bone mass after renal transplant with preemptive care.Transplant Proc. 1998; 30: 1327-1328Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, six demonstrated improvements in BMD,19Feber J. Cochat P. Braillon P. et al.Bone mineral density after renal transplantation in children.J Pediatr. 1994; 6: 870-875Abstract Full Text Full Text PDF Scopus (68) Google Scholar, 27Moreno A. Torregrosa J.V. Pons F. et al.Bone mineral density after renal transplantation.Transplant Proc. 1999; 31: 2322-2323Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 38Nowacka-Cieciura E. Durlik M. Cieciura T. et al.Steroid withdrawal after renal transplantation-risks and benefits.Transplant Proc. 2002; 34: 560-563Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 42Yazawa K. Ishikawa T. Ichikawa Y. et al.Positive effects of kidney transplantation on bone mass.Transplant Proc. 1998; 30: 3031-3033Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 43Kim H. Chang K. Lee T. et al.Bone mineral density after renal transplantation.Transplant Proc. 1998; 30: 3029-3030Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 44Cueto-Manzano A.M. Konel S. Freemont A.J. et al.Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation.Am J Kidney Dis. 2000; 35: 227-236Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar one showed a miniscule improvement in BMD at the lumbar spine that was accompanied by a minor decline at the femoral neck,45Grotz W.H. Rump L.C. Niessen A. et al.Treatment of osteopenia and osteoporosis after kidney transplantation.Transplantation. 1998; 66: 1004-1008Crossref PubMed Scopus (111) Google Scholar and two found variability among patient outcomes.46Cruz D. Wysolmerski J.J. Brickel H. et al.Parameters of high bone-turnover predict bone loss in renal transplant patients A longitudinal study.Transplantation. 2001; 72: 83-88Crossref PubMed Scopus (45) Google Scholar, 47Brandenburg V.M. Ketteler M. Fassbender W.J. et al.Development of lumbar bone mineral density in the late course after kidney transplantation.Am J Kidney Dis. 2002; 40: 1066-1074Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In one of the latter two studies, Cruz et al46Cruz D. Wysolmerski J.J. Brickel H. et al.Parameters of high bone-turnover predict bone loss in renal transplant patients A longitudinal study.Transplantation. 2001; 72: 83-88Crossref PubMed Scopus (45) Google Scholar noted that allograft recipients with worsening BMDs had laboratory values suggestive of high bone turnover, whereas patients with stable BMDs did not. Unfortunately, although some reports have noted improved BMDs after the first year of transplantation, the vast majority of studies indicate that BMDs measured up to 12 years after transplantation are persistently diminished.11Parker C.R. Freemont A.J. Blackwell P.J. et al.Cross-sectional analysis of renal transplantation osteoporosis.J Bone Miner Res. 1999; 14: 1943-1951Crossref PubMed Scopus (73) Google Scholar, 30Kokado Y. Takahara S. Ichimaru N. et al.Factors influencing vertebral bone density after renal transplantation.Transpl Int. 2000; 13: S431-S435Crossref PubMed Google Scholar, 36Grotz W.H. Mundinger F.A. Gugel B. et al.Bone mineral density after kidney transplantation. A cross-sectional study in 190 graft recipients up to 20 years after tran