Alendronate versus Calcitriol for Prevention of Bone Loss after Cardiac Transplantation
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《新英格兰医药杂志》
To the Editor: Shane et al. (Feb. 19 issue)1 found minimal differences between the benefits conferred by alendronate and those conferred by calcitriol, and the authors speculated (as did Lindsay, in an accompanying Perspective article2) that combination therapy might improve the response. There is good evidence in the literature on postmenopausal osteoporosis of a synergistic effect when calcitriol is used in combination with an antiresorptive agent (a bisphosphonate or estrogen), as shown in studies of calcitriol combined with cyclical etidronate,3 with alendronate,4 or with estrogen.5,6 The two studies of estrogen both showed significant benefits of the combination, as compared with estrogen alone, at the total hip and trochanter (both weight-bearing and chiefly cortical sites), with no adverse effects at the forearm or spine. Advantages over estrogen have also been shown with respect to the bone mineral density of the total body (excluding the head) — another chiefly cortical measurement.6 Bone loss after organ transplantation is multifactorial and commonly severe, as it was in the study by Shane et al. (untreated loss at the femoral neck, 6.2 percent at one year).1 Prevention of bone loss by monotherapy is uncommon. There are thus persuasive reasons for further trials of combination therapy after organ transplantation.
Donald H. Gutteridge, F.R.A.C.P.
Sir Charles Gairdner Hospital
6009 Nedlands, Australia
dhgutteridge@bigpond.com
References
Shane E, Addesso V, Namerow PB, et al. Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 2004;350:767-776.
Lindsay R. Bone loss after cardiac transplantation. N Engl J Med 2004;350:751-754.
Masud T, Mulcahy B, Thompson AV, et al. Effects of cyclical etidronate combined with calcitriol versus cyclical etidronate alone on spine and femoral neck bone mineral density in postmenopausal osteoporotic women. Ann Rheum Dis 1998;57:346-349.
Frediani B, Allegri A, Bisogno S, Marcolongo R. Effects of combined treatment with calcitriol plus alendronate on bone mass and bone turnover in postmenopausal osteoporosis. Clin Drug Invest 1998;15:235-44.
Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab 2001;86:3618-3628.
Gutteridge DH, Holzherr ML, Retallack RW, et al. A randomized trial comparing hormone replacement therapy (HRT) and HRT plus calcitriol in the treatment of postmenopausal osteoporosis with vertebral fractures: benefit of the combination on total body and hip density. Calcif Tissue Int 2003;73:33-43.
To the Editor: Shane et al. report that alendronate and calcitriol have equal efficacy in the prevention of bone loss during the first year after cardiac transplantation. Several points should be clarified. First, the creatinine clearance fell to 30 ml per minute or less in about one quarter of the patients. Because renal failure can affect the efficacy of both drugs, the evolution of bone mass in the two groups should have been documented separately for patients with renal failure and those without it. Second, the tapering of immunosuppression depends on graft tolerance. Were the yearly cumulative intakes of prednisolone and cyclosporine similar in the two groups? The calcineurin inhibitor used predominantly was cyclosporine; since tacrolimus might have lesser effect on bone itself because it permits lower corticosteroid requirements,1,2 the number of patients given tacrolimus should be mentioned. Third, we were surprised that three patients (in the alendronate group) were withdrawn because of "excessive bone loss" (the primary end point). Finally, factors affecting post-transplantation bone mass, such as the prevalence of diabetes, the rate of intake of osteogenic drugs (thiazides or statins), the prevalence of premenopausal women with a resumption of post-transplantation ovarian cycles, and post-transplantation levels of physical activity should be compared between the groups.
Agnès Dejardin, M.D.
Jean-Pierre Devogelaer, M.D.
Eric Goffin, M.D.
Université Catholique de Louvain
1200 Brussels, Belgium
goffin@nefr.ucl.ac.be
References
Goffin E, Devogelaer JP, Depresseux G, Squifflet JP, Pirson Y, van Yperselede de Strihou C. Evaluation of bone mineral density after renal transplantation under a tacrolimus-based immunosuppression: a pilot study. Clin Nephrol 2003;59:190-195.
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;357:342-347.
To the Editor: Shane et al. conclude that alendronate may be more attractive than calcitriol for the prevention of bone loss after cardiac transplantation, mainly because of the high incidence of hypercalciuria (27 percent) in the calcitriol group. However, it should be noted that it is rather unusual to combine calcitriol treatment with the use of a vitamin D–containing calcium preparation instead of a supplement containing calcium alone. This therapeutic regimen added 1000 IU of vitamin D per day to calcitriol and may have been responsible for the high rate of hypercalciuria in that group.
The unexpected positive results in patients treated with calcitriol may have been influenced by a high incidence of renal impairment. In our patients, we reduce the target levels of cyclosporine more rapidly than did Shane et al., and renal impairment occurs considerably less frequently in our patients at an even later point after cardiac transplantation.1
Guenter Hoefle, M.D.
Hannes Holzmueller, M.D.
Heinz Drexel, M.D.
Landeskrankenhaus Feldkirch
A-6807 Feldkirch, Austria
guenter.hoefle@lkhf.at
References
Hofle G, Holzmuller H, Gouya G, et al. Lower serum beta-CrossLaps in male cardiac transplant recipients treated without prednisolone. Transpl Int 2003;16:523-528.
Dr. Shane replies: Dr. Gutteridge suggests that the combination of alendronate and calcitriol might be more effective than monotherapy. A study of combination therapy would be of interest, since no published study has compared transplant recipients treated with bisphosphonates and those treated with both bisphosphonates and calcitriol during the first year after transplantation. However, I respectfully submit that monotherapy was rather effective in preventing bone loss, and the prescription of two drugs cannot be justified unless a positive effect on the incidence of fracture can be demonstrated.
I disagree with Dr. Hoefle and colleagues that 1000 IU of vitamin D might explain the hypercalciuria in the calcitriol group. The mean serum concentrations of 25-hydroxyvitamin D were normal at randomization (22 ng per milliliter) and at 12 months (39 ng per milliliter) (normal range, 9 to 52 ng per milliliter). The affinity of the vitamin D receptor for 1,25-dihydroxyvitamin D is 1000 times as high as its affinity for 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D is considerably more important in terms of biologic effects on calcium metabolism. Sambrook and colleagues noted an increased frequency of hypercalciuria (59 percent) in cardiac-transplant recipients who were treated with similar doses of calcitriol and who did not receive parent vitamin D.1 Transient episodes of renal impairment were equally distributed between the two treatment groups. Serum creatinine levels were only mildly elevated in the calcitriol group, and the mean creatinine clearance was greater than 65 ml per minute throughout the study. It is not clear how mild renal impairment could account for the positive results with calcitriol.
In response to Dr. Dejardin and colleagues: the declines in creatinine clearance were generally transient. At each study visit, the mean creatinine clearance ranged between 60 and 68 ml per minute and did not differ between the groups. Therefore, we did not analyze the results separately. In our transplantation program, cyclosporine is used to induce immunosuppression. By 12 months, tacrolimus was substituted in 17 percent of the patients in an equal distribution according to treatment assignment. As we pointed out in the Discussion section of our article, our results may not be applicable to transplantation programs in which different regimens are used. We did not calculate the cumulative intake of prednisone and cyclosporine because of inaccuracies inherent in such estimates. At all time points, however, daily intakes of all immunosuppressive drugs were similar. The three patients who withdrew from the alendronate group met predefined safety criteria (confirmed bone loss of 8 percent or more at six months and a T score below –2.0). We were unaware of their treatment assignments and their data were included in the intention-to-treat analysis. All the patients received statins, and none received thiazides. We cannot provide data on diabetes or physical activity. The small number of women (10 premenopausal and 17 postmenopausal) precluded separate presentation of these data. However, rates of bone loss did not differ according to sex or menopausal status.
Elizabeth Shane, M.D.
Columbia University College of Physicians and Surgeons
New York, NY 10032
References
Sambrook P, Henderson NK, Keogh A, et al. Effect of calcitriol on bone loss after cardiac or lung transplantation. J Bone Miner Res 2000;15:1818-1824.
Donald H. Gutteridge, F.R.A.C.P.
Sir Charles Gairdner Hospital
6009 Nedlands, Australia
dhgutteridge@bigpond.com
References
Shane E, Addesso V, Namerow PB, et al. Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 2004;350:767-776.
Lindsay R. Bone loss after cardiac transplantation. N Engl J Med 2004;350:751-754.
Masud T, Mulcahy B, Thompson AV, et al. Effects of cyclical etidronate combined with calcitriol versus cyclical etidronate alone on spine and femoral neck bone mineral density in postmenopausal osteoporotic women. Ann Rheum Dis 1998;57:346-349.
Frediani B, Allegri A, Bisogno S, Marcolongo R. Effects of combined treatment with calcitriol plus alendronate on bone mass and bone turnover in postmenopausal osteoporosis. Clin Drug Invest 1998;15:235-44.
Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab 2001;86:3618-3628.
Gutteridge DH, Holzherr ML, Retallack RW, et al. A randomized trial comparing hormone replacement therapy (HRT) and HRT plus calcitriol in the treatment of postmenopausal osteoporosis with vertebral fractures: benefit of the combination on total body and hip density. Calcif Tissue Int 2003;73:33-43.
To the Editor: Shane et al. report that alendronate and calcitriol have equal efficacy in the prevention of bone loss during the first year after cardiac transplantation. Several points should be clarified. First, the creatinine clearance fell to 30 ml per minute or less in about one quarter of the patients. Because renal failure can affect the efficacy of both drugs, the evolution of bone mass in the two groups should have been documented separately for patients with renal failure and those without it. Second, the tapering of immunosuppression depends on graft tolerance. Were the yearly cumulative intakes of prednisolone and cyclosporine similar in the two groups? The calcineurin inhibitor used predominantly was cyclosporine; since tacrolimus might have lesser effect on bone itself because it permits lower corticosteroid requirements,1,2 the number of patients given tacrolimus should be mentioned. Third, we were surprised that three patients (in the alendronate group) were withdrawn because of "excessive bone loss" (the primary end point). Finally, factors affecting post-transplantation bone mass, such as the prevalence of diabetes, the rate of intake of osteogenic drugs (thiazides or statins), the prevalence of premenopausal women with a resumption of post-transplantation ovarian cycles, and post-transplantation levels of physical activity should be compared between the groups.
Agnès Dejardin, M.D.
Jean-Pierre Devogelaer, M.D.
Eric Goffin, M.D.
Université Catholique de Louvain
1200 Brussels, Belgium
goffin@nefr.ucl.ac.be
References
Goffin E, Devogelaer JP, Depresseux G, Squifflet JP, Pirson Y, van Yperselede de Strihou C. Evaluation of bone mineral density after renal transplantation under a tacrolimus-based immunosuppression: a pilot study. Clin Nephrol 2003;59:190-195.
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;357:342-347.
To the Editor: Shane et al. conclude that alendronate may be more attractive than calcitriol for the prevention of bone loss after cardiac transplantation, mainly because of the high incidence of hypercalciuria (27 percent) in the calcitriol group. However, it should be noted that it is rather unusual to combine calcitriol treatment with the use of a vitamin D–containing calcium preparation instead of a supplement containing calcium alone. This therapeutic regimen added 1000 IU of vitamin D per day to calcitriol and may have been responsible for the high rate of hypercalciuria in that group.
The unexpected positive results in patients treated with calcitriol may have been influenced by a high incidence of renal impairment. In our patients, we reduce the target levels of cyclosporine more rapidly than did Shane et al., and renal impairment occurs considerably less frequently in our patients at an even later point after cardiac transplantation.1
Guenter Hoefle, M.D.
Hannes Holzmueller, M.D.
Heinz Drexel, M.D.
Landeskrankenhaus Feldkirch
A-6807 Feldkirch, Austria
guenter.hoefle@lkhf.at
References
Hofle G, Holzmuller H, Gouya G, et al. Lower serum beta-CrossLaps in male cardiac transplant recipients treated without prednisolone. Transpl Int 2003;16:523-528.
Dr. Shane replies: Dr. Gutteridge suggests that the combination of alendronate and calcitriol might be more effective than monotherapy. A study of combination therapy would be of interest, since no published study has compared transplant recipients treated with bisphosphonates and those treated with both bisphosphonates and calcitriol during the first year after transplantation. However, I respectfully submit that monotherapy was rather effective in preventing bone loss, and the prescription of two drugs cannot be justified unless a positive effect on the incidence of fracture can be demonstrated.
I disagree with Dr. Hoefle and colleagues that 1000 IU of vitamin D might explain the hypercalciuria in the calcitriol group. The mean serum concentrations of 25-hydroxyvitamin D were normal at randomization (22 ng per milliliter) and at 12 months (39 ng per milliliter) (normal range, 9 to 52 ng per milliliter). The affinity of the vitamin D receptor for 1,25-dihydroxyvitamin D is 1000 times as high as its affinity for 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D is considerably more important in terms of biologic effects on calcium metabolism. Sambrook and colleagues noted an increased frequency of hypercalciuria (59 percent) in cardiac-transplant recipients who were treated with similar doses of calcitriol and who did not receive parent vitamin D.1 Transient episodes of renal impairment were equally distributed between the two treatment groups. Serum creatinine levels were only mildly elevated in the calcitriol group, and the mean creatinine clearance was greater than 65 ml per minute throughout the study. It is not clear how mild renal impairment could account for the positive results with calcitriol.
In response to Dr. Dejardin and colleagues: the declines in creatinine clearance were generally transient. At each study visit, the mean creatinine clearance ranged between 60 and 68 ml per minute and did not differ between the groups. Therefore, we did not analyze the results separately. In our transplantation program, cyclosporine is used to induce immunosuppression. By 12 months, tacrolimus was substituted in 17 percent of the patients in an equal distribution according to treatment assignment. As we pointed out in the Discussion section of our article, our results may not be applicable to transplantation programs in which different regimens are used. We did not calculate the cumulative intake of prednisone and cyclosporine because of inaccuracies inherent in such estimates. At all time points, however, daily intakes of all immunosuppressive drugs were similar. The three patients who withdrew from the alendronate group met predefined safety criteria (confirmed bone loss of 8 percent or more at six months and a T score below –2.0). We were unaware of their treatment assignments and their data were included in the intention-to-treat analysis. All the patients received statins, and none received thiazides. We cannot provide data on diabetes or physical activity. The small number of women (10 premenopausal and 17 postmenopausal) precluded separate presentation of these data. However, rates of bone loss did not differ according to sex or menopausal status.
Elizabeth Shane, M.D.
Columbia University College of Physicians and Surgeons
New York, NY 10032
References
Sambrook P, Henderson NK, Keogh A, et al. Effect of calcitriol on bone loss after cardiac or lung transplantation. J Bone Miner Res 2000;15:1818-1824.