Original Article
Alendronate versus Calcitriol for the Prevention of Bone Loss after Cardiac Transplantation
N Engl J Med 2004; 350:767-776February 19, 2004
- Abstract
Background
Osteoporosis is a well-known complication of cardiac transplantation. We conducted a randomized trial comparing alendronate with calcitriol for the prevention of bone loss during the first year after cardiac transplantation.
Methods
A total of 149 patients were randomly assigned to receive either alendronate (10 mg per day) or calcitriol (0.5 μg per day) a mean (±SD) of 21±11 days after transplantation. Estimates of bone loss and the incidence of fractures among untreated patients were obtained from a reference group of 27 prospectively recruited patients who received cardiac transplants within the same period as the intervention groups.
Results
At one year, the bone mineral density at the lumbar spine had decreased by a mean of 0.7 percent in the alendronate group and 1.6 percent in the calcitriol group (P=0.25 for the test of no difference). The bone mineral density at the femoral neck decreased by a mean of 1.7 percent in the alendronate group and 2.1 percent in the calcitriol group (P=0.69). In the reference group, the mean bone mineral density at the lumbar spine decreased by 3.2 percent (P=0.03 for the comparison with the alendronate group; P=0.15 for the comparison with the calcitriol group), and the mean density at the femoral neck decreased by 6.2 percent (P=0.001 for comparisons with both intervention groups). The incidence of vertebral fractures did not differ significantly among the groups (6.8 percent in the alendronate group, 3.6 percent in the calcitriol group, and 13.6 percent in the reference group). Hypercalciuria developed in 27 percent of the patients in the calcitriol group and 7 percent of those in the alendronate group (P=0.01).
Conclusions
The degree of bone loss and the rates of fracture did not differ significantly between the intervention groups. Calcitriol was associated with a higher risk of hypercalciuria. Alendronate-treated patients sustained less bone loss at the spine than those in the reference group, and both intervention groups sustained less bone loss at the hip than the reference group. The requirement for monitoring the serum and urinary calcium levels in calcitriol-treated patients makes alendronate more attractive for the prevention of bone loss early after cardiac transplantation.
Media in This Article
Figure 1
Study Profile.Figure 2
Intention-to-Treat Analysis of the Mean (±SE) Percent Change in Bone Mineral Density from Base Line.Article Activity
- Article
Osteoporosis is a well-known complication of cardiac transplantation.1 Rapid bone loss is reported consistently during the first year after transplantation.2-5 The prevalence of fractures ranges from 22 to 44 percent among cardiac-transplant recipients,6-9 and the incidence of vertebral fractures during the first three years after transplantation ranges from 18 to 35 percent.10,11 We conducted an interventional study with the aim of preventing bone loss after heart transplantation. We judged that the previously reported high rates of fracture necessitated a study comparing two active agents. We selected calcitriol and the bisphosphonate alendronate, which have both been shown to prevent glucocorticoid-induced osteoporosis.12-14 On the basis of published results with calcitriol15-17 and our previous experience with bisphosphonates,18 we hypothesized that alendronate would be more effective than calcitriol.
Methods
Study Design
In this one-year, double-placebo, double-blind study, patients who had undergone cardiac transplantation within the previous 30 days were randomly assigned to receive either active alendronate (Fosamax, 10 mg per day) and a placebo matching the calcitriol or active calcitriol (Rocaltrol, 0.25 μg twice daily) and a placebo matching the alendronate. Patients who declined to participate in the randomized study but who completed all study measurements constituted the reference group. All patients received calcium (945 mg per day) and vitamin D (1000 IU per day).
Men and women (of all races and ethnic groups, 18 to 70 years of age), who underwent cardiac transplantation at Columbia–Presbyterian Medical Center in New York or Newark–Beth Israel Medical Center in New Jersey were eligible. The criteria for exclusion were the presence of primary hyperparathyroidism, cancer, thyrotoxicosis, sarcoidosis, a serum creatinine concentration of more than 2.5 mg per deciliter (221 μmol per liter) by one month after transplantation, active peptic ulcer disease, nephrolithiasis, hormone-replacement therapy initiated within the previous year, or the use of bisphosphonates or calcitonin therapy. Base-line measurements of bone mineral density, radiographs of the spine, fasting serum, and 24-hour urine specimens were obtained immediately after transplantation. The measurement of bone density was repeated at 6 and 12 months, and radiography was repeated at 12 months. The primary efficacy end points were the percent changes in the bone mineral density of the lumbar spine and the femoral neck at 6 and 12 months. The primary safety end points included the serum calcium and creatinine levels and the urinary calcium and creatinine clearance at 2, 6, 9, and 12 months. The secondary outcome variables included the incidence of vertebral fractures, the serum parathyroid hormone level, and the serum N-telopeptide level.
The study was conducted in the Irving Center for Clinical Research, Metabolic Bone Diseases and Cardiac Transplantation Units of the Columbia–Presbyterian Medical Center, with the approval of the institutional review boards of the Columbia–Presbyterian Medical Center and the Newark–Beth Israel Medical Center. Written informed consent was obtained from all participants.
Recruitment and Retention of Patients
Of 432 patients who received a heart transplant between January 1999 and June 2001 (390 at the Columbia–Presbyterian Medical Center and 42 at the Newark–Beth Israel Medical Center), 212 were deemed ineligible (Figure 1Figure 1
Study Profile.), most commonly because they were enrolled in another clinical trial or were younger than 18 years of age. Sixty-five patients declined to participate, of whom 27 constituted the reference group.Six patients who underwent randomization and two patients in the reference group died of transplantation-related complications (rejection, infection, or heart failure). Eighteen patients who underwent randomization withdrew before the 6-month visit, and five withdrew before the 12-month visit. Excluding the patients who died, the rate of retention for 12 months was 85 percent in the alendronate group and 83 percent in the calcitriol group (Figure 1). A total of 66 percent of the patients in the alendronate group completed 12 months of study treatment, as did 52 percent of those in the calcitriol group. The reasons for the discontinuation of the study treatment were gastrointestinal symptoms (in 4 patients in the alendronate group and 11 in the calcitriol group), the patient's wishes (in 4 patients, all in the calcitriol group), excessive bone loss at six months (in 3 patients, all in the alendronate group), severe transplantation-related complications (in 1 patient in the alendronate group), nephrolithiasis (in 1 patient in the alendronate group), severe hypercalcemia (in 2 patients, both in the calcitriol group), enrollment in another trial (in 2 patients in the alendronate group and 1 in the calcitriol group), use of testosterone therapy (in 1 patient in the alendronate group) or alendronate therapy (in 1 patient in the calcitriol group), and renal insufficiency (in 1 patient in the alendronate group).
Immunosuppression
All patients received glucocorticoids and calcineurin inhibitors, predominantly cyclosporine. Intravenous methylprednisolone was followed by oral prednisone, beginning at a dose of 50 mg and tapering to 30 mg by two weeks and to 5 to 10 mg by six months. Prednisone treatment was not discontinued in any of the patients. Rejection was managed with the use of high-dose oral or intravenous glucocorticoids. The trough blood cyclosporine levels were maintained between 250 and 300 ng per milliliter for the first six months and between 200 and 250 ng per milliliter for the second six months.
Bone Density and Biochemical Measurements
Bone density was measured with the use of dual-energy x-ray absorptiometry (QDR-4500 densitometer, Hologic) at Columbia–Presbyterian Medical Center; the short-term in vivo coefficient of variation is 0.68 percent for the spine and 1.36 percent for the femoral neck. Bone density was expressed in grams per square centimeter and in terms of T and z scores for the comparison of patients with young–normal and age-matched populations of the same race and sex. According to the criteria defined by a World Health Organization study group for white postmenopausal women, a T score of –2.5 or below indicates the presence of osteoporosis.19 Radiography was performed according to the protocol for the Study of Osteoporotic Fractures.20 New fractures,21 defined by a 20 percent decrease (≥4 mm) in any vertebral height,22 were adjudicated by a skeletal radiologist.22
All biochemical variables were measured in fasting, morning serum by means of an autoanalyzer (Technicon Instruments). Urinary calcium excretion was analyzed by means of colorimetry, and creatinine excretion by means of an autoanalyzer. Aliquots of serum were stored at –70°C for batch analyses of parathyroid hormone and N-telopeptide levels in the core laboratory with the use of a two-site immunoradiometric assay (Corning-Nichols Institute) and an enzyme-linked immunosorbent assay (Osteomark, Ostex), respectively.
Adverse Events
At each visit, medication use, side effects of the study drugs, and adverse events (including hospitalization, rejection, infection, gastrointestinal symptoms, hypercalcemia, hypercalciuria, and fracture) were documented through history taking and a review of the chart. Occurrences of nonvertebral fractures were ascertained through the review of radiographs.
If the serum calcium level exceeded 10.4 mg per deciliter (2.6 mmol per liter) or the urinary calcium excretion exceeded 400 mg per 24 hours (10 mmol per day), calcium supplementation was reduced by one tablet (315 mg) per day. If the elevation persisted after all calcium supplementation was discontinued, the dose of calcitriol or matching placebo was reduced sequentially by 0.25 μg per day. On resolution of hypercalcemia or hypercalciuria, the patient was rechallenged with the previous dose. If the abnormality recurred, the patient was given the lower dose. The average dose of calcitriol over the 12-month study period, including that in patients who remained in the study but discontinued treatment with the study medications, was 0.37±0.22 μg per day.
Gastrointestinal symptoms, which can be caused by mycophenolate mofetil therapy and cytomegalovirus, are common after transplantation. Since alendronate is also associated with gastrointestinal symptoms,23 we discontinued treatment with alendronate or matching placebo in patients who had such symptoms. Gastrointestinal symptoms that resolved after the discontinuation of alendronate therapy and recurred after the resumption of treatment were considered likely to be related to alendronate. If the symptoms were not controlled by omeprazole therapy or were intolerable, the study medications were discontinued but the patient remained in the study.
A bone loss of 8 percent or more at the six-month visit prompted repeated scanning. If the loss was confirmed and the T score was below –2.0, the patient was withdrawn from the study and referred for evaluation. An independent data and safety board monitored the study end points and safety. Merck had no role in the design, conduct, or analysis of the study.
Statistical Analysis
The study was designed to detect differences between the groups of 2.5 percentage points (a standard deviation of 5 percent) in the percent change from base line to 12 months in the bone mineral density at the spine and femoral neck, with a power of 80 percent and a two-tailed P value of 0.05. The sample size would permit the detection of a 15 percent difference in the incidence of vertebral fractures (with a power of 80 percent) if the fracture rate was 20 percent in one group and 5 percent in the other group.
Base-line differences between the groups were assessed with the use of Student's t-test for continuous variables and Fisher's exact test for categorical variables. The percent change from base line in the bone density was tested with a mixed-model analysis of variance for repeated measures; the covariates were the fixed effect of treatment (to test the overall differences between treatments), the interaction between treatment and time (to test for differences between the groups in the percent changes at 6 and 12 months), random effects of patient and error, and the base-line bone density. Fixed effects with P values of less than 0.05 were investigated through the calculation of differences between the groups within a given period and differences within each group over time, with their 95 percent confidence intervals. The differences between groups in immunosuppression and biochemical variables were examined by means of a mixed-model analysis of variance. Adverse events and new fractures were assessed with the use of Fisher's exact test. The primary analyses compared the two randomized groups. Secondary analyses compared the randomized groups with the reference group.
All efficacy and safety analyses were conducted according to the intention-to-treat principle. Per-protocol analyses included patients who adhered to study treatment and completed the 6-month or 12-month visit. A two-sided P value of 0.05 or less was required for the rejection of the null hypothesis. The data were held and analyzed by the investigative team.
Results
Study Population
The mean age of the patients was 54 years, and patients were predominantly male and white. The randomized groups did not differ significantly in terms of age, sex, race or ethnic group, or base-line bone density (Table 1Table 1
Base-Line Characteristics of the Patients.). The T score for the lumbar spine was –2.5 or lower in 6.5 percent of the women and 7.8 percent of the men. The reference group was similar to the intervention groups in all respects.Immunosuppression
The daily doses of prednisone and cyclosporine and the trough cyclosporine levels (Table 2Table 2
Immunosuppressive Therapy in the Patients.) did not differ significantly among the groups, except that the dose of cyclosporine was lower in the alendronate group than in the other groups at randomization and was lower in the reference group than in the other groups at nine months.Change in Bone Mineral Density
Neither the intention-to-treat analysis (Figure 2Figure 2
Intention-to-Treat Analysis of the Mean (±SE) Percent Change in Bone Mineral Density from Base Line.) nor the per-protocol analysis (data not shown) revealed significant differences between the calcitriol and alendronate groups at 6 or 12 months. By 12 months, the bone density of the spine had decreased by 0.7 percent in the alendronate group (95 percent confidence interval for the change, –1.8 to 0.5; the positive value indicates that there was an increase in bone density in one or more patients) and by 1.6 percent in the calcitriol group (95 percent confidence interval, –2.8 to –0.5). The bone density at the femoral neck decreased by 1.7 percent in the alendronate group (95 percent confidence interval, –3.1 to –0.4) and by 2.1 percent in the calcitriol group (95 percent confidence interval, –3.5 to –0.8). The bone density of the total hip decreased by 1.5 percent in the alendronate group (95 percent confidence interval, –2.1 to –0.5) and by 2.3 percent in the calcitriol group (95 percent confidence interval, –2.9 to –0.8). At 12 months, the estimated difference between the changes in the two groups was 0.9 percentage point for the change at the spine (95 percent confidence interval, –0.7 to 2.6; P=0.25), 0.4 percentage point for the change at the femoral neck (95 percent confidence interval, –1.5 to 2.3; P=0.69), and 0.8 percentage point for the change at the total hip (95 percent confidence interval, –0.7 to 2.2; P=0.31).Secondary analyses revealed that the bone loss at the spine was greater in the reference group (a decrease of 3.2 percent; 95 percent confidence interval, –5.0 to –1.4 percent) than in the alendronate group (estimated difference, 2.5 percentage points; 95 percent confidence interval, 0.4 to 4.6; P=0.03), but there was no significant difference between the reference group and the calcitriol group (estimated difference, 1.6 percentage points; 95 percent confidence interval, –0.5 to 3.6; P=0.15). Among the patients in the calcitriol group who adhered to therapy, the bone density decreased by only 0.5 percent (95 percent confidence interval, –1.9 to 0.8), and the difference between this calcitriol subgroup and the reference group of 2.7 percentage points (95 percent confidence interval, 0.3 to 4.8) was significant (P=0.03).
The bone loss at the femoral neck in the reference group (a decrease of 6.2 percent; 95 percent confidence interval, –8.0 to –4.4) and the loss at the total hip in this group (a decrease of 4.6 percent; 95 percent confidence interval, –6.1 to –3.2) were significantly greater than those in both intervention groups. For the femoral neck, the estimated difference between the alendronate group and the reference group was 4.5 percentage points (95 percent confidence interval, 2.3 to 6.7; P=0.001), and the estimated difference between the calcitriol group and the reference group was 4.1 percentage points (95 percent confidence interval, 1.6 to 6.6; P=0.001). For the total hip, the estimated difference between the alendronate group and the reference group was 3.1 percentage points (95 percent confidence interval, 1.4 to 4.8; P=0.001), and the estimated difference between the calcitriol group and the reference group was 2.3 percentage points (95 percent confidence interval, 0.1 to 4.5; P=0.04).
Fractures
Radiographs of the spine were available for 59 patients in the alendronate group (80 percent), 56 in the calcitriol group (75 percent), and 22 in the reference group (81 percent). The rates of fracture in the three groups were not statistically different. Four patients in the alendronate group (6.8 percent of those with radiographs) sustained a total of eight fractures, and two patients in the calcitriol group (3.6 percent of those with radiographs) sustained two fractures (difference, 3.2 percentage points; 95 percent confidence interval, –6.6 to 13.0; P=0.68). Two patients in the alendronate group (3.4 percent) and no patients in the calcitriol group had multiple fractures (difference, 3.4 percentage points; 95 percent confidence interval, –3.0 to 9.8; P=0.10). Nonvertebral fractures occurred in four patients in the alendronate group and four in the calcitriol group.
Three patients in the reference group (13.6 percent of those with radiographs) sustained a total of eight fractures; two patients in this group (9.1 percent) had multiple fractures. Although there were more fractures in the reference group, the number of fractures was small. The differences between the reference group and the alendronate group in the proportion of patients with any fracture (6.8 percentage points; 95 percent confidence interval, –25.7 to 12.0; P=0.68) and in the proportion of patients with multiple fractures (5.7 percentage points; 95 percent confidence interval, –21.7 to 10.3; P=0.30) were not significant. Similarly, the differences between the reference group and the calcitriol group in the proportion of patients with any fracture (10.0 percentage points; 95 percent confidence interval, –28.7 to 8.2; P=0.14) and in the proportion of patients with multiple fractures (9.1 percentage points; 95 percent confidence interval, –24.3 to 6.1; P=0.08) were not significant.
Adverse Events
There were no significant differences between the intervention groups in the rates of transplantation-related or gastrointestinal adverse events (Table 3Table 3
Patients with Adverse Events.). More patients in the calcitriol group than in the alendronate group required adjustments of the calcium and calcitriol doses; hypercalciuria and hypercalcemia also developed in more patients in the calcitriol group. One patient in the calcitriol group withdrew from the study because of severe hypercalcemia (serum calcium level, 12.2 mg per deciliter [3.04 mmol per liter]).Biochemical Indexes of Mineral Metabolism
The base-line serum N-telopeptide level, a marker of bone resorption, was elevated in all groups (25.5±1.6 nmol bone collagen equivalents per liter; normal range, 7.7 to 19.3); the level then decreased to the mid-normal range in both intervention groups, while remaining elevated in the reference group (Figure 3AFigure 3
Mean Percent Change in the Serum N-Telopeptide Level (Panel A) and Mean Change in the Serum Parathyroid Hormone Level (Panel B).). By six months, the serum parathyroid hormone level (Figure 3B) had decreased in the calcitriol group (from 44±5 to 29±5 pg per milliliter [4.4±1.1 to 3.2±1.1 pmol per liter]) and had increased in the alendronate group (from 39±4 to 51±4 pg per milliliter [4.3±0.4 to 5.6±0.4 pmol per liter]; P<0.001 for the comparison between groups). The pattern of change in the reference group was similar to that in the alendronate group.Discussion
We directly compared alendronate and calcitriol for the prevention of bone loss during the first year after cardiac transplantation. The primary analysis revealed no significant differences between the intervention groups in terms of bone loss or the incidence of fractures. However, patients who were treated with either drug had significantly less bone loss at the hip than patients in the reference group, and those who received alendronate had less bone loss at the spine than those in the reference group, suggesting that both alendronate and calcitriol prevent bone loss after heart transplantation. Although fewer fractures occurred in patients in the intervention groups than in those in the reference group, the differences were not significant. Hypercalcemia and hypercalciuria were more common and severe in patients in the calcitriol group.
Bone loss occurring shortly after heart transplantation is probably related to concomitant therapy with high-dose glucocorticoids and calcineurin inhibitors, particularly cyclosporine.24 Glucocorticoids profoundly inhibit bone formation, with relatively minor effects on bone resorption.25 In contrast, studies of calcineurin inhibitors in animals have demonstrated markedly increased bone resorption and formation.26 Elevated levels of markers of bone resorption have consistently been demonstrated in heart-transplant recipients who receive both glucocorticoids and cyclosporine3,4,27,28; such a pattern is not generally seen in patients taking glucocorticoids alone.29 Both alendronate and calcitriol suppressed resorption, as evidenced by similar decreases in serum N-telopeptide levels. However, alendronate directly inhibits osteoclast activity, whereas calcitriol appears to act by suppressing parathyroid hormone secretion.
Previous studies of heart-transplant recipients treated with pharmacologic doses of vitamin D or bisphosphonates suggested that alendronate would have greater efficacy than calcitriol. In patients receiving alfacalcidol, bone density decreased by 5 to 7 percent at the spine and femoral neck.15 Similar losses were reported in calcitriol-treated patients after heart or lung transplantation.16 Sambrook et al. reported one-year bone loss at the spine of only 2.3 percent among patients treated with calcitriol (0.5 μg per day), as compared with 2.9 percent among patients given placebo.17 However, bone loss at the femoral neck averaged 3.9 percent in the calcitriol group, as compared with 6.6 percent in the placebo group.17 In contrast, smaller studies evaluating intravenous bisphosphonates (pamidronate) after heart transplantation reported stable or improved bone density at the spine18,30 or smaller losses (1.4 to 1.9 percent).31 Pamidronate and ibandronate also prevent bone loss after kidney,32,33 liver,34-36 and lung37 transplantation.
Although we originally hypothesized that alendronate would be superior to calcitriol, we observed clinically and statistically insignificant differences of 1.0 percentage point or less at all sites. The study's power to detect differences of this magnitude was approximately 10 percent. Calcitriol appeared to be more effective than previously reported,15-17,31 perhaps because in earlier studies supplemental calcium was not provided,16 the calcitriol doses were lower,17 or higher doses of glucocorticoids were used. Moreover, the rates of bone loss and fracture in the reference group were lower than expected, perhaps because the prednisone doses were considerably lower than those used in earlier studies.2,3,10,11
Both alendronate and calcitriol were tolerated well with respect to transplantation-related adverse events. The rates of adverse gastrointestinal effects, which may limit the use of oral bisphosphonates, were similar in the two groups. Hypercalcemia and hypercalciuria in patients receiving calcitriol were usually mild and easily managed. However, if intensive monitoring had not been incorporated into the study design, the severity and frequency of these adverse effects would undoubtedly have been greater. Lower doses of calcitriol or supplemental calcium might ameliorate this problem, but such improvement might come at the expense of efficacy. Combining a lower dose of calcitriol with a bisphosphonate might prevent the increase in the parathyroid hormone level and permit alendronate to be more effective. Since considerable bone loss may occur during the first weeks after transplantation, an intravenous bisphosphonate administered immediately after transplantation might have proved more effective than calcitriol.
Our study has several limitations. It is common for studies of interventions for post-transplantation osteoporosis to lack a randomized control group; we believed that ethical considerations required the design we used. Fortunately, the reference group provided a benchmark for interpreting the effects of the interventions. The rather high rate of nonadherence (only about 60 percent of the patients were receiving their assigned therapy at 12 months) appeared to be attributable mainly to transplantation-related adverse events. Since analyses including only patients who adhered to therapy were generally similar to the intention-to-treat analyses, nonadherence did not appear to affect the results materially. Finally, since the study was conducted predominantly in a single institution and included only heart-transplant recipients, the results may not apply to other centers or other types of organ transplantation.
In summary, bone loss appeared to be minimal when alendronate or calcitriol therapy was initiated during the first month after heart transplantation. Although our results did not establish any difference in efficacy, both drugs appeared to be safe and prevented some of the bone loss that occurred in a reference group of patients who received transplants concurrently. However, the requirement for monitoring the serum and urinary calcium levels in patients receiving calcitriol may make alendronate the more attractive choice in the complicated setting of the early post-transplantation period.
Supported by grants (AR-41391 and RR-006645) from the National Institutes of Health and by a Medical School Grant from Merck.
Dr. Shane reports having received a grant from Novartis. Dr. Zucker reports having receive consulting fees from Bristol-Myers Squibb, Novartis, and INO Therapeutics, lecture fees from GlaxoSmithKline and Medtronics, and grants from Fujisawa and Wyeth.
We are indebted to Merck, Rahway, N.J., for providing matched alendronate and placebo, to Hoffmann–LaRoche Pharmaceuticals, Nutley, N.J., for providing matched calcitriol and placebo, and to Mission–Pharmacal, San Antonio, Tex., for providing Citracal+D; to the members of the data and safety monitoring board, Murray Favus, M.D. (chair), Keith Aaronson, M.D., Steven Cummings, M.D., KyungMann Kim, Ph.D., and Lawrence Raisz, M.D.; to the physicians and nurses of the cardiac transplantation programs of Columbia–Presbyterian Medical Center and Newark–Beth Israel Medical Center for their support; to Dr. Joan McGowan, director of the Bone Biology Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, for her support; and to Dr. John Bilezikian and Dr. Shonni Silverberg for helpful discussions.
Source Information
From the Departments of Medicine (E.S., V.A., D.J.M., S.M., D.M.), Biostatistics (S.-H.L.), and Radiology (R.B.S.), College of Physicians and Surgeons, and the Department of Population and Family Health, Mailman School of Public Health (P.B.N.), Columbia University, New York; and the Department of Medicine, Newark–Beth Israel Medical Center, Newark, N.J. (M.Z., S.P.).
Address reprint requests to Dr. Shane at the Department of Medicine, PH8-864, Columbia University College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032.
- References
References
1
Shane E ,Epstein S . Transplantation osteoporosis. Transplant Rev 2001;15:11-32
CrossRef2
Sambrook PN ,Kelly PJ ,Keogh AM , et al. Bone loss after cardiac transplantation: a prospective study. J Heart Lung Transplant 1994;13:116-121
Web of Science | Medline3
Shane E ,Rivas M ,McMahon DJ , et al. Bone loss and turnover after cardiac transplantation. J Clin Endocrinol Metab 1997;82:1497-1506
CrossRef | Web of Science | Medline4
Thiebaud D ,Kreig M ,Gillard-Berguer D ,Jaquet A ,Goy JJ ,Burckhardt P . Cyclosporine induces high bone turnover and may contribute to bone loss after heart transplantation. Eur J Clin Invest 1996;26:549-555
CrossRef | Web of Science | Medline5
Van Cleemput J ,Daenen W ,Nijs J ,Geusens P ,Dequeker J ,Vanhaecke J . Timing and quantification of bone loss in cardiac transplant recipients. Transpl Int 1995;8:196-200
CrossRef | Web of Science | Medline6
Glendenning P ,Kent GN ,Adler BD , et al. High prevalence of osteoporosis in cardiac transplant recipients and discordance between biochemical turnover markers and bone histomorphometry. Clin Endocrinol (Oxf) 1999;50:347-355
CrossRef | Web of Science | Medline7
Ramsey-Goldman R ,Dunn JE ,Dunlop DD , et al. Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res 1999;14:456-463
CrossRef | Web of Science | Medline8
Shane E ,Rivas MC ,Silverberg SJ ,Kim TS ,Staron RB ,Bilezikian JP . Osteoporosis after cardiac transplantation. Am J Med 1993;94:257-264
CrossRef | Web of Science | Medline9
Rich GM ,Mudge GH ,Laffel GL ,LeBoff MS . Cyclosporine A and prednisone-associated osteoporosis in heart transplant recipients. J Heart Lung Transplant 1992;11:950-958
Web of Science | Medline10
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
CrossRef | Web of Science | Medline11
Shane E ,Rivas M ,Staron RB , et al. Fracture after cardiac transplantation: a prospective longitudinal study. J Clin Endocrinol Metab 1996;81:1740-1746
CrossRef | Web of Science | Medline12
Sambrook P ,Birmingham J ,Kelly P , et al. Prevention of corticosteroid osteoporosis: a comparison of calcium, calcitriol, and calcitonin. N Engl J Med 1993;328:1747-1752
Full Text | Web of Science | Medline13
Sambrook PN ,Kotowicz M ,Nash P , 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;18:919-924
CrossRef | Web of Science | Medline14
Saag KG ,Emkey R ,Schnitzer TJ , et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998;339:292-299
Full Text | Web of Science | Medline15
Van Cleemput J ,Daenen W ,Geusens P ,Dequeker P ,Van De Werf F ,VanHaecke J . Prevention of bone loss in cardiac transplant recipients: a comparison of bisphosphonates and vitamin D. Transplantation 1996;61:1495-1499
CrossRef | Web of Science | Medline16
Henderson K ,Eisman J ,Keogh A , et al. Protective effect of short-term calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation. J Bone Miner Res 2001;16:565-571
CrossRef | Web of Science | Medline17
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
CrossRef | Web of Science | Medline18
Shane E ,Rodino MA ,McMahon DJ , et al. Prevention of bone loss after heart transplantation with antiresorptive therapy: a pilot study. J Heart Lung Transplant 1998;17:1089-1096
Web of Science | Medline19
Kanis JA . Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. Osteoporos Int 1994;4:368-381
CrossRef | Web of Science | Medline20
Black DM ,Palermo L ,Nevitt MC , et al. Comparison of methods for defining prevalent vertebral deformities: the Study of Osteoporotic Fractures. J Bone Miner Res 1995;10:890-902
CrossRef | Web of Science | Medline21
Wu CY ,Li J ,Jergas M ,Genant HK . Comparison of semiquantitative and quantitative techniques for the assessment of prevalent and incident vertebral fractures. Osteoporos Int 1995;5:354-370
CrossRef | Web of Science | Medline22
Genant HK ,Jergas M ,Palermo L , et al. Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res 1996;11:984-996
CrossRef | Web of Science | Medline23
Baker DE . Alendronate and risedronate: what you need to know about their upper gastrointestinal tract toxicity. Rev Gastroenterol Disord 2002;2:20-33
Medline24
Cohen A ,Shane E . Osteoporosis after solid organ and bone marrow transplantation. Osteoporos Int 2003;14:617-630
CrossRef | Web of Science | Medline25
Canalis E ,Delany AM . Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci 2002;966:73-81
CrossRef | Web of Science | Medline26
Epstein S ,Dissanayake IR ,Goodman GR , et al. Effect of the interaction of parathyroid hormone and cyclosporine A on bone mineral metabolism in the rat. Calcif Tissue Int 2001;68:240-247
CrossRef | Web of Science | Medline27
Sambrook PN ,Kelly PJ ,Fontana D , et al. Mechanisms of rapid bone loss following cardiac transplantation. Osteoporos Int 1994;4:273-276
CrossRef | Web of Science | Medline28
Valimaki MJ ,Kinnunen K ,Tahtela R , et al. A prospective study of bone loss and turnover after cardiac transplantation: effect of calcium supplementation with or without calcitonin. Osteoporos Int 1999;10:128-136
CrossRef | Web of Science | Medline29
Lems WF ,Gerrits MI ,Jacobs JWG ,van Vugt RM ,van Rijn HJM ,Bijlsma JWJ . Changes in (markers of) bone metabolism during high dose corticosteroid pulse treatment in patients with rheumatoid arthritis. Ann Rheum Dis 1996;55:288-293
CrossRef | Web of Science | Medline30
Krieg M ,Seydoux C ,Sandini L , et al. Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study. Osteoporos Int 2001;12:112-116
CrossRef | Web of Science | Medline31
Bianda T ,Linka A ,Junga G , et al. Prevention of osteoporosis in heart transplant recipients: a comparison of calcitriol with calcitonin and pamidronate. Calcif Tissue Int 2000;67:116-121
CrossRef | Web of Science | Medline32
Fan S ,Almond MK ,Ball E ,Evans K ,Cunningham J . Pamidronate therapy as prevention of bone loss following renal transplantation. Kidney Int 2000;57:684-690
CrossRef | Web of Science | Medline33
Kovac D ,Lindic J ,Kandus A ,Bren AF . Prevention of bone loss in kidney graft recipients. Transplant Proc 2001;33:1144-1145
CrossRef | Web of Science | Medline34
Reeves HL ,Francis RM ,Manas DM ,Hudson M ,Day CP . Intravenous bisphosphonate prevents symptomatic osteoporotic vertebral collapse in patients after liver transplantation. Liver Transpl Surg 1998;4:404-409
CrossRef | Medline35
Giannini S ,Dangel A ,Carraro G , et al. Alendronate prevents further bone loss in renal transplant recipients. J Bone Miner Res 2001;16:2111-2117
CrossRef | Web of Science | Medline36
Hommann M ,Abendroth K ,Lehmann G , et al. Effect of transplantation on bone: osteoporosis after liver and multivisceral transplantation. Transplant Proc 2002;34:2296-2298
CrossRef | Web of Science | Medline37
Aris RM ,Lester GE ,Renner JB , et al. Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation. Am J Respir Crit Care Med 2000;162:941-946
Web of Science | Medline
- Citing Articles (59)
Citing Articles
1
Carolina A. Moreira Kulak, Victoria Z. Cochenski Borba, Jaime Kulak Júnior, Melani Ribeiro Custódio. (2011) Osteoporosis After Transplantation. Current Osteoporosis Reports
CrossRef2
L. E. Nikkel, S. Mohan, A. Zhang, D. J. McMahon, S. Boutroy, G. Dube, B. Tanriover, D. Cohen, L. Ratner, C. S. Hollenbeak, M. B. Leonard, E. Shane, T. L. Nickolas. (2011) Reduced Fracture Risk With Early Corticosteroid Withdrawal After Kidney Transplant. American Journal of Transplantationno-no
CrossRef3
Melania Martínez-Morillo, Dolors Grados, Susana Holgado. (2011) Premenopausal Osteoporosis: How to Treat?. Reumatolog ía Cl ínica (English Edition)
CrossRef4
Melania Martínez-Morillo, Dolors Grados, Susana Holgado. (2011) Osteoporosis premenopáusica: ¿cómo tratarla?. Reumatología Clínica
CrossRef5
E. M. Stein, E. Shane. (2011) Vitamin D in organ transplantation. Osteoporosis International 22:7, 2107-2118
CrossRef6
Khashayar Sakhaee. (2011) Osteoporosis following organ transplantation: pathogenesis, diagnosis and management. Expert Review of Endocrinology & Metabolism 6:2, 157-176
CrossRef7
Elizabeth A Kendrick, Connie L Davis. 2011. Management of the Successful Solid Organ Transplant Recipient. , 73-102.
CrossRef8
J.-V. Torregrosa, D. Fuster, A. Monegal, M. Á. Gentil, J. Bravo, L. Guirado, A. Muxí, J. Cubero. (2011) Efficacy of low doses of pamidronate in osteopenic patients administered in the early post-renal transplant. Osteoporosis International 22:1, 281-287
CrossRef9
Emily M. Stein, Elizabeth Shane. 2011. Vitamin D and Organ Transplantation. , 1291-1298.
CrossRef10
Maria Rosa Costanzo, Maria Rosa Costanzo, Anne Dipchand, Randall Starling, Allen Anderson, Michael Chan, Shashank Desai, Savitri Fedson, Patrick Fisher, Gonzalo Gonzales-Stawinski, Luigi Martinelli, David McGiffin, Francesco Parisi, Jon Smith, David Taylor, Bruno Meiser, Steven Webber, David Baran, Michael Carboni, Thomas Dengler, David Feldman, Maria Frigerio, Abdallah Kfoury, Daniel Kim, Jon Kobashigawa, Michael Shullo, Josef Stehlik, Jeffrey Teuteberg, Patricia Uber, Andreas Zuckermann, Sharon Hunt, Michael Burch, Geetha Bhat, Charles Canter, Richard Chinnock, Marisa Crespo-Leiro, Reynolds Delgado, Fabienne Dobbels, Kathleen Grady, Kao W, Jaqueline Lamour, Gareth Parry, Jignesh Patel, Daniela Pini, Sean Pinney, Jeffrey Towbin, Gene Wolfel, Diego Delgado, Howard Eisen, Lee Goldberg, Jeff Hosenpud, Maryl Johnson, Anne Keogh, Clive Lewis, John O'Connell, Joseph Rogers, Heather Ross, Stuart Russell, Johan Vanhaecke. (2010) The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. The Journal of Heart and Lung Transplantation 29:8, 914-956
CrossRef11
M. Matsubara, E. Yamachika, H. Tsujigiwa, N. Mizukawa, T. Ueno, J. Murakami, N. Ishida, Y. Kaneda, N. Shirasu, S. Takagi. (2010) Suppressive effects of 1,4-dihydroxy-2-naphthoic acid administration on bone resorption. Osteoporosis International 21:8, 1437-1447
CrossRef12
L. J. Peppone, S. Hebl, J. Q. Purnell, M. E. Reid, R. N. Rosier, K. M. Mustian, O. G. Palesh, A. J. Huston, M. N. Ling, G. R. Morrow. (2010) The efficacy of calcitriol therapy in the management of bone loss and fractures: a qualitative review. Osteoporosis International 21:7, 1133-1149
CrossRef13
Ashok K. Bhalla. (2010) Management of osteoporosis in a pre-menopausal woman. Best Practice & Research Clinical Rheumatology 24:3, 313-327
CrossRef14
Pascale Schwab, Sarah Lipton, Gail S. Kerr. (2010) Rheumatologic sequelae and challenges in organ transplantation. Best Practice & Research Clinical Rheumatology 24:3, 329-340
CrossRef15
P. Sun, D. H. Cai, Q. N. Li, H. Chen, W. M. Deng, L. He, L. Yang. (2010) Effects of Alendronate and Strontium Ranelate on Cancellous and Cortical Bone Mass in Glucocorticoid-Treated Adult Rats. Calcified Tissue International 86:6, 495-501
CrossRef16
Liv Forli, Jens Bollerslev, Svein Simonsen, Gunhild A. Isaksen, Kari E. Kvamsdal, Kristin Godang, Gaut Gadeholt, Are H. Pripp, Oystein Bjortuft. (2010) Dietary Vitamin K2 Supplement Improves Bone Status After Lung and Heart Transplantation. Transplantation 89:4, 458-464
CrossRef17
E STEIN. 2010. Transplantation Osteoporosis. , 443-452.
CrossRef18
A GIUSTI. 2010. Treatment of Male Osteoporosis with Bisphosphonates. , 667-679.
CrossRef19
Emily M. Stein, Adi Cohen, Matthew Freeby, Halley Rogers, Shannon Kokolus, Vanessa Scott, Donna Mancini, Susan Restaino, Robert Brown, Donald J. McMahon, Elizabeth Shane. (2009) Severe vitamin D deficiency among heart and liver transplant recipients. Clinical Transplantation 23:6, 861-865
CrossRef20
J. D. Ringe, E. Schacht. (2009) Potential of alfacalcidol for reducing increased risk of falls and fractures. Rheumatology International 29:10, 1177-1185
CrossRef21
Pantelis Panopalis, Jinoos Yazdany. (2009) Bone health in systemic lupus erythematosus. Current Rheumatology Reports 11:3, 177-184
CrossRef22
S. KITAZAKI, K. MITSUYAMA, J. MASUDA, K. HARADA, H. YAMASAKI, K. KUWAKI, H. TAKEDATSU, G. SUGIYAMA, O. TSURUTA, M. SATA. (2009) Clinical trial: comparison of alendronate and alfacalcidol in glucocorticoid-associated osteoporosis in patients with ulcerative colitis. Alimentary Pharmacology & Therapeutics 29:4, 424-430
CrossRef23
H WARD. (2009) Nutritional and Metabolic Issues in Solid Organ Transplantation: Targets for Future Research. Journal of Renal Nutrition 19:1, 111-122
CrossRef24
R.O. Ritchie, K.J. Koester, S. Ionova, W. Yao, N.E. Lane, J.W. Ager. (2008) Measurement of the toughness of bone: A tutorial with special reference to small animal studies. Bone 43:5, 798-812
CrossRef25
Jessica Fleischer, Donald J. McMahon, Wylie Hembree, Vicki Addesso, Christopher Longcope, Elizabeth Shane. (2008) Serum Testosterone Levels After Cardiac Transplantation. Transplantation 85:6, 834-839
CrossRef26
Katharina Kerschan-Schindl, Margot Ruzicka, Stephane Mahr, Matthias Paireder, Christian Krestan, Andreas Gleiss, Christian Bieglmayer, Veronika Fialka-Moser, Richard Pacher, Michael Grimm, Peter Pietschmann. (2008) Unexpected low incidence of vertebral fractures in heart transplant recipients: analysis of bone turnover. Transplant International 21:3, 255-262
CrossRef27
G. Ayoub, T. Bardin. (2008) Complicaciones osteoarticulares de los trasplantes de
rganos. EMC - Aparato Locomotor 41:1, 1-8
CrossRef28
Emily Stein, Peter Ebeling, Elizabeth Shane. (2007) Post-Transplantation Osteoporosis. Endocrinology & Metabolism Clinics of North America 36:4, 937-963
CrossRef29
T. Matsunaga, M. Shigetomi, T. Hashimoto, H. Suzuki, T. Gondo, H. Tanaka, T. Sugiyama, T. Taguchi. (2007) Effects of bisphosphonate treatment on bone repair under immunosuppression using cyclosporine A in adult rats. Osteoporosis International 18:11, 1531-1540
CrossRef30
J. Pascual, J. Torrealba, J. Myers, S. Tome, M. Samaniego, A. Musat, A. Djamali. (2007) Collapsing focal segmental glomerulosclerosis in a liver transplant recipient on alendronate. Osteoporosis International 18:10, 1435-1438
CrossRef31
Damaris Vega, Khashayar Sakhaee. (2007) Osteoporosis following solid organ transplantation. Future Rheumatology 2:4, 341-345
CrossRef32
M. Bodingbauer, T. Wekerle, B. Pakrah, P. Roschger, M. Peck-Radosavljevic, G. Silberhumer, S. Grampp, S. Rockenschaub, G. Berlakovich, R. Steininger, K. Klaushofer, R. Oberbauer, F. Mühlbacher. (2007) Prophylactic Bisphosphonate Treatment Prevents Bone Fractures After Liver Transplantation. American Journal of Transplantation 7:7, 1763-1769
CrossRef33
Luigi Gennari, John P. Bilezikian. (2007) Osteoporosis in Men. Endocrinology & Metabolism Clinics of North America 36:2, 399-419
CrossRef34
Peter R. Ebeling. (2007) Transplantation osteoporosis. Current Osteoporosis Reports 5:1, 29-37
CrossRef35
Johann D. Ringe, Parvis Farahmand. (2007) Advances in the management of corticosteroid-induced osteoporosis with bisphosphonates. Clinical Rheumatology 26:4, 474-484
CrossRef36
Ilkka Helenius, Hannu Jalanko, Ville Remes, Sari Salminen, Heikki Sairanen, Christer Holmberg, Jari Peltonen. (2007) Therapy Insight: orthopedic complications after solid organ transplantation in childhood. Nature Clinical Practice Nephrology 3:2, 96-105
CrossRef37
Jean-Pierre Devogelaer. (2006) Glucocorticoid-Induced Osteoporosis: Mechanisms and Therapeutic Approach. Rheumatic Disease Clinics of North America 32:4, 733-757
CrossRef38
C. F. McDonald, R. M. D. Zebaze, E. Seeman. (2006) Calcitriol does not prevent bone loss in patients with asthma receiving corticosteroid therapy: a double-blind placebo-controlled trial. Osteoporosis International 17:10, 1546-1551
CrossRef39
de Nijs, Ron N.J., Jacobs, Johannes W.G., Lems, Willem F., Laan, Roland F.J., Algra, Ale, Huisman, Anne-Margriet, Buskens, Erik, de Laet, Chris E.D., Oostveen, Ans C.M., Geusens, Piet P.M.M., Bruyn, George A.W., Dijkmans, Ben A.C., Bijlsma, Johannes W.J., . (2006) Alendronate or Alfacalcidol in Glucocorticoid-Induced Osteoporosis. New England Journal of Medicine 355:7, 675-684
Full Text40
Randy W. Braith, Peter M. Magyari, Michael N. Fulton, Clem F. Lisor, Sara E. Vogel, James A. Hill, Juan M. Aranda. (2006) Comparison of Calcitonin versus Calcitonin + Resistance Exercise as Prophylaxis for Osteoporosis in Heart Transplant Recipients. Transplantation 81:8, 1191-1195
CrossRef41
Armin Zittermann, Stefanie S. Schleithoff, Reiner Koerfer. (2006) Markers of bone metabolism in congestive heart failure. Clinica Chimica Acta 366:1-2, 27-36
CrossRef42
Adi Cohen, Vicki Addesso, Donald J. McMahon, Ronald B. Staron, Pearila Namerow, Simon Maybaum, Donna Mancini, Elizabeth Shane. (2006) Discontinuing Antiresorptive Therapy One Year after Cardiac Transplantation: Effect on Bone Density and Bone Turnover. Transplantation 81:5, 686-691
CrossRef43
Ilkka Helenius, Ville Remes, Sari Salminen, Helena Valta, Outi Mäkitie, Christer Holmberg, Petri Palmu, Pekka Tervahartiala, Seppo Sarna, Miia Helenius, Jari Peltonen, Hannu Jalanko. (2006) Incidence and Predictors of Fractures in Children After Solid Organ Transplantation: A 5-Year Prospective, Population-Based Study. Journal of Bone and Mineral Research 21:3, 380-387
CrossRef44
Jean-Pierre Devogelaer, Stefan Goemaere, Steven Boonen, Jean-Jacques Body, Jean-Marc Kaufman, Jean-Yves Reginster, Serge Rozenberg, Yves Boutsen. (2006) Evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club. Osteoporosis International 17:1, 8-19
CrossRef45
M. Ramos Solchaga, L. Gil Fraguas. (2006) Trasplante cardíaco y rehabilitación. Rehabilitación 40:6, 345-352
CrossRef46
Rose Christian, Karen E Hansen. (2005) Transplant osteoporosis. Current Opinion in Orthopaedics 16:5, 382-386
CrossRef47
Pierre D Delmas. (2005) The use of bisphosphonates in the treatment of osteoporosis. Current Opinion in Internal Medicine 4:5, 512-516
CrossRef48
Shojiro Akahoshi, Akinori Sakai, Shinobu Arita, Satoshi Ikeda, Yoshiomi Morishita, Hideki Tsutsumi, Masako Ito, Ayako Shiraishi, Toshitaka Nakamura. (2005) Modulation of bone turnover by alfacalcidol and/or alendronate does not prevent glucocorticoid-induced osteoporosis in growing minipigs. Journal of Bone and Mineral Metabolism 23:5, 341-350
CrossRef49
Günter Höfle, Hannes Holzmüller, Heinz Drexel. (2005) Bisphosphonates Routine in Prevention of Post-Transplant Osteoporosis?. Journal of Bone and Mineral Research 20:8, 1482-1482
CrossRef50
Gunda Millonig, Ivo W. Graziadei, Dagmar Eichler, Karl-Peter Pfeiffer, Gerd Finkenstedt, Petra Muehllechner, Alfred Koenigsrainer, Raimund Margreiter, Wolfgang Vogel. (2005) Alendronate in combination with calcium and vitamin D prevents bone loss after orthotopic liver transplantation: A prospective single-center study. Liver Transplantation 11:8, 960-966
CrossRef51
Ira Pande, David J. Hosking. (2005) Oral antiresorptive therapy. Current Rheumatology Reports 7:1, 71-77
CrossRef52
Adi Cohen, Philip Sambrook, Elizabeth Shane. (2004) Management of Bone Loss After Organ Transplantation. Journal of Bone and Mineral Research 19:12, 1919-1932
CrossRef53
Ira Pande, David J. Hosking. (2004) Oral antiresorptive therapy. Current Osteoporosis Reports 2:4, 116-122
CrossRef54
Yves F.C. Smets, Johan W. de Fijter, Jan Ringers, Herman H.P.J. Lemkes, Neveen A.T. Hamdy. (2004) Long-term follow-up study on bone mineral density and fractures after simultaneous pancreas-kidney transplantation. Kidney International 66:5, 2070-2076
CrossRef55
Michelle A. Josephson, L Philip Schumm, May Y. Chiu, Cory Marshall, J Richard Thistlethwaite, Stuart M. Sprague. (2004) Calcium and Calcitriol Prophylaxis Attenuates Posttransplant Bone Loss. Transplantation 78:8, 1233-1236
CrossRef56
Sheila A Doggrell. (2004) Recent important clinical trials of drugs in osteoporosis. Expert Opinion on Pharmacotherapy 5:7, 1635-1638
CrossRef57
(2004) Alendronate versus Calcitriol for Prevention of Bone Loss after Cardiac Transplantation. New England Journal of Medicine 350:22, 2306-2308
Full Text58
E. Seeman. (2004) Clinical and Basic Research Papers - January and February Selections. International Bone and Mineral Society Knowledge Environment 1:5, 1-4
CrossRef59
Lindsay, Robert, . (2004) Bone Loss after Cardiac Transplantation. New England Journal of Medicine 350:8, 751-754
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- Letters
