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Osteoporosis after organ transplantation
CORRESPONDENCE
Osteoporosis after organ transplantation 2
Sir—Gudrun Leidig-Bruckner and colleagues (Feb 3, p 342)1 report a high frequency of osteoporotic fractures in cardiac or liver allograft recipients. Age and lumbar mineral-density decrease were the only independent predictors at multivariate analysis. They saw no dose-dependent effect of glucocorticoids, but most events occurred in the first year after transplantation, when glucocorticoids are given at higher doses. However, differences between patients given glucocorticoids might be difficult to identify, since most transplant patients received standard doses. The best way to assess the role of glucocorticoids would be to compare patients assigned glucocorticoids with those who receive none. We prospectively measured, every 6 months, bone-mineral density (with dual-energy X-ray absorptiometry) of lumbar vertebrae in 53 renal-transplant recipients randomly assigned cyclosporine alone (13 patients), cyclosporine plus steroids (20), or cyclosporine plus steroids plus azathioprine (20).2 In patients given steroid-free immunosuppression, the bone-mineral density increased significantly from transplant to 18 months post-transplant, which suggests that cyclosporine does not interfere with bone mineralisation. In the two glucocorticoid-treated groups, bonemineral density decreased significantly by 18 months. In a multicentre study, our intention-to-treat analysis showed the cumulative risk of bone complications was significantly lower at 4 years in patients given steroid-free immunosuppression than in those given steroids.3 The causes of osteoporotic fractures in organ-transplant recipients is multifactorial, but glucocorticoids might play a major part. Since there is now evidence that, at least in kidney transplantation, steroid-free immunosuppression with cyclosporine, tacrolimus,4 or rapamune5 is feasible and does not affect graft survival, patients at higher risk of osteoporosis, such as malnourished or immobilised patients, should be considered for such a treatment. *Claudio Ponticelli, Adriana Aroldi Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore de Milano, via della Commenda 15, 20122 Milan, Italy (e-mail: [email protected]) 1
Leidig-Bruckner G, Hosch S, Dodidou P, et al. Frequency and predictors of
THE LANCET • Vol 357 • May 19, 2001
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osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Lancet 2001; 357: 342–47. Aroldi A, Tarantino A, Montagnino B, Cesana B, Cocucci C, Ponticelli C. Effect of three immunosuppressive regimens on vertebral bone density in renal transplant recipients. Transplantation 1997; 63: 380–86. Ponticelli C, Tarantino X, Segoloni GP, et al. A randomized study comparing three cyclosporine-based regimens in cadaveric renal transplantation. J Am Soc Nephrol 1997; 8: 638–46. Shapiro R, Jordan NIL, Scantlebury VP, et al. Outcome after steroid withdrawal in renal transplant patients receiving tacrolimus-based immunosuppression. Transpl Proc 1998; 30: 1375–77. Kahan BD, Podbielski J, Napoli KC, Katz SM, Meier-Kriesche HU, von Buren CT. Immunosuppressive effects and safety of a sirolimus cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040–46.
Sir—Gudrun Leidig-Bruckner and colleagues1 note a predisposing role for osteoporosis. In an accompanying Commentary, P Delmas (Feb 3, p 325)2 emphasises the necessity to assess bone-mineral density in transplant candidates and the need to develop effective therapeutic strategies for osteoporosis in these high-risk patients. The development of new immunosuppressive agents could contribute to this endeavour. We have assessed the evolution of bone-mineral density in the first 12 months after renal transplantation in 23 patients given an immunosuppression regimen combining tacrolimus and low-dose prednisolone (mean 1-year cumulative prednisolone intake 2412 mg [SD 618]). We measured bone-mineral density of lumbar spine, total hip, and hip subregions (neck, trochanter, intertrochanter, Ward’s triangle) by dual-energy X-ray absorptiometry within the first 15 days, and 1 year after transplantation.3 Density remained unchanged in the lumbar and in the trochanter subregions, and rose slightly, although not significantly, in the other investigated sites. Among the 23 patients, bone-mineral density increased by at least 2% in eight, 13, ten, and ten patients in the lumbar, neck, trochanter and total hip subregions, respectively. These results contrast with the loss of bone-mineral density commonly reported with cyclosporine-prednisolone based protocols.4,5 We saw no correlation between evolution of bonemineral density and age, sex, dialysis duration, parathormone concentration at transplantation, prednisolone and tacrolimus cumulative doses, or calcium, vitamin D, and hormonereplacement therapy prescription.
In this context, the finding by Leidig-Bruckner that the number of patients with at least one vertebral fracture was lower in the tacrolimus than in the cyclosporine group (5 vs 20%) is especially noteworthy even if this difference is not significant. The tailoring of immunosuppressive therapy might help to prevent posttransplantation osteoporosis. *E Goffin, J P Devogelaer, G Depresseux, J P Squifflet, Y Pirson Departments of *Nephrology, Rheumatology, and Renal Transplantation, Cliniques St Luc, University Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium 1
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Leidig-Bruckner G, Hosch S, Dodidou P, et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Lancet 2001; 357: 342–47. Delmas PD. Osteoporosis in patients with organ transplants: a neglected problem. Lancet 2001; 357: 325–26. Goffin E, Devogelaer JP, Depresseux G, Squifflet JP, Pirson Y. Does a tacrolimusbased immunosuppression protect bone mineral density after renal transplantation? J Am Soc Nephrol 2000; 11: 718A. Julian BA, Laskow DA, Dubowsky J, et al. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991; 325: 544–50. Almond MK, Kwan JTC, Evans K, Cunningham J. Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 1994; 66: 52–57.
Sir—Given the findings of Gudrun Leidig-Bruckner and colleagues,1 we should reconsider carefully the role of calcium supplements in prevention of osteoporotic fractures. Osteoporosis is caused by the disintegration of bone matrix, and osteomalacia by lack of mineralisation. Calcium is inevitably lost when mineralised matrix disintegrates. This substance is crucial during the development of bone, but it cannot replace disintegrating matrix or prevent its loss.2 As Heaney3 has pointed out, calcium is a nutrient and not a drug, and the only disorder it can be expected to alleviate is calcium deficiency. Excess calcium supplementation will suppress the secretion of parathyroid hormone and slow the natural turnover of bone. Fossilised bone is at risk from microfractures. Calcium intakes of 1·0–1·5 g daily, commonly recommended for postmenopausal women, are associated with an increased rather than a decreased risk of fracture.4 Although bone-mineral density is lower in Chinese and other Oriental populations than in white people, the incidence of hip fractures is lower.5 The low bone-mineral density is related to low consumption of calcium, especially from dairy products. Not surprisingly,
1623
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Osteoporosis after organ transplantation 2
Sir—Gudrun Leidig-Bruckner and colleagues (Feb 3, p 342)1 report a high frequency of osteoporotic fractures in cardiac or liver allograft recipients. Age and lumbar mineral-density decrease were the only independent predictors at multivariate analysis. They saw no dose-dependent effect of glucocorticoids, but most events occurred in the first year after transplantation, when glucocorticoids are given at higher doses. However, differences between patients given glucocorticoids might be difficult to identify, since most transplant patients received standard doses. The best way to assess the role of glucocorticoids would be to compare patients assigned glucocorticoids with those who receive none. We prospectively measured, every 6 months, bone-mineral density (with dual-energy X-ray absorptiometry) of lumbar vertebrae in 53 renal-transplant recipients randomly assigned cyclosporine alone (13 patients), cyclosporine plus steroids (20), or cyclosporine plus steroids plus azathioprine (20).2 In patients given steroid-free immunosuppression, the bone-mineral density increased significantly from transplant to 18 months post-transplant, which suggests that cyclosporine does not interfere with bone mineralisation. In the two glucocorticoid-treated groups, bonemineral density decreased significantly by 18 months. In a multicentre study, our intention-to-treat analysis showed the cumulative risk of bone complications was significantly lower at 4 years in patients given steroid-free immunosuppression than in those given steroids.3 The causes of osteoporotic fractures in organ-transplant recipients is multifactorial, but glucocorticoids might play a major part. Since there is now evidence that, at least in kidney transplantation, steroid-free immunosuppression with cyclosporine, tacrolimus,4 or rapamune5 is feasible and does not affect graft survival, patients at higher risk of osteoporosis, such as malnourished or immobilised patients, should be considered for such a treatment. *Claudio Ponticelli, Adriana Aroldi Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore de Milano, via della Commenda 15, 20122 Milan, Italy (e-mail: [email protected]) 1
Leidig-Bruckner G, Hosch S, Dodidou P, et al. Frequency and predictors of
THE LANCET • Vol 357 • May 19, 2001
3
4
5
osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Lancet 2001; 357: 342–47. Aroldi A, Tarantino A, Montagnino B, Cesana B, Cocucci C, Ponticelli C. Effect of three immunosuppressive regimens on vertebral bone density in renal transplant recipients. Transplantation 1997; 63: 380–86. Ponticelli C, Tarantino X, Segoloni GP, et al. A randomized study comparing three cyclosporine-based regimens in cadaveric renal transplantation. J Am Soc Nephrol 1997; 8: 638–46. Shapiro R, Jordan NIL, Scantlebury VP, et al. Outcome after steroid withdrawal in renal transplant patients receiving tacrolimus-based immunosuppression. Transpl Proc 1998; 30: 1375–77. Kahan BD, Podbielski J, Napoli KC, Katz SM, Meier-Kriesche HU, von Buren CT. Immunosuppressive effects and safety of a sirolimus cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040–46.
Sir—Gudrun Leidig-Bruckner and colleagues1 note a predisposing role for osteoporosis. In an accompanying Commentary, P Delmas (Feb 3, p 325)2 emphasises the necessity to assess bone-mineral density in transplant candidates and the need to develop effective therapeutic strategies for osteoporosis in these high-risk patients. The development of new immunosuppressive agents could contribute to this endeavour. We have assessed the evolution of bone-mineral density in the first 12 months after renal transplantation in 23 patients given an immunosuppression regimen combining tacrolimus and low-dose prednisolone (mean 1-year cumulative prednisolone intake 2412 mg [SD 618]). We measured bone-mineral density of lumbar spine, total hip, and hip subregions (neck, trochanter, intertrochanter, Ward’s triangle) by dual-energy X-ray absorptiometry within the first 15 days, and 1 year after transplantation.3 Density remained unchanged in the lumbar and in the trochanter subregions, and rose slightly, although not significantly, in the other investigated sites. Among the 23 patients, bone-mineral density increased by at least 2% in eight, 13, ten, and ten patients in the lumbar, neck, trochanter and total hip subregions, respectively. These results contrast with the loss of bone-mineral density commonly reported with cyclosporine-prednisolone based protocols.4,5 We saw no correlation between evolution of bonemineral density and age, sex, dialysis duration, parathormone concentration at transplantation, prednisolone and tacrolimus cumulative doses, or calcium, vitamin D, and hormonereplacement therapy prescription.
In this context, the finding by Leidig-Bruckner that the number of patients with at least one vertebral fracture was lower in the tacrolimus than in the cyclosporine group (5 vs 20%) is especially noteworthy even if this difference is not significant. The tailoring of immunosuppressive therapy might help to prevent posttransplantation osteoporosis. *E Goffin, J P Devogelaer, G Depresseux, J P Squifflet, Y Pirson Departments of *Nephrology, Rheumatology, and Renal Transplantation, Cliniques St Luc, University Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium 1
2
3
4
5
Leidig-Bruckner G, Hosch S, Dodidou P, et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Lancet 2001; 357: 342–47. Delmas PD. Osteoporosis in patients with organ transplants: a neglected problem. Lancet 2001; 357: 325–26. Goffin E, Devogelaer JP, Depresseux G, Squifflet JP, Pirson Y. Does a tacrolimusbased immunosuppression protect bone mineral density after renal transplantation? J Am Soc Nephrol 2000; 11: 718A. Julian BA, Laskow DA, Dubowsky J, et al. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991; 325: 544–50. Almond MK, Kwan JTC, Evans K, Cunningham J. Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 1994; 66: 52–57.
Sir—Given the findings of Gudrun Leidig-Bruckner and colleagues,1 we should reconsider carefully the role of calcium supplements in prevention of osteoporotic fractures. Osteoporosis is caused by the disintegration of bone matrix, and osteomalacia by lack of mineralisation. Calcium is inevitably lost when mineralised matrix disintegrates. This substance is crucial during the development of bone, but it cannot replace disintegrating matrix or prevent its loss.2 As Heaney3 has pointed out, calcium is a nutrient and not a drug, and the only disorder it can be expected to alleviate is calcium deficiency. Excess calcium supplementation will suppress the secretion of parathyroid hormone and slow the natural turnover of bone. Fossilised bone is at risk from microfractures. Calcium intakes of 1·0–1·5 g daily, commonly recommended for postmenopausal women, are associated with an increased rather than a decreased risk of fracture.4 Although bone-mineral density is lower in Chinese and other Oriental populations than in white people, the incidence of hip fractures is lower.5 The low bone-mineral density is related to low consumption of calcium, especially from dairy products. Not surprisingly,
1623
For personal use. Only reproduce with permission from The Lancet Publishing Group.