- Email: [email protected]
Bone Fractures After Cardiac Transplantation
Bone Fractures After Cardiac Transplantation M. Luaces, M.G. Crespo Leiro, M.J. Paniagua Martin, J. Garcia de Lara, R. Marzoa Rivas, P. Piñon Esteban, G. Cursak, R. Rı´os, C. Naya Leira, J.J. Alonso, and A. Castro Beiras ABSTRACT Objective. Bone loss and bone fractures are disabling complications after heart transplantation. Severe bone loss happens mainly during the first year posttransplantation. Steroids and cyclosporine alter bone metabolism in several ways. To counterbalance these effects, antiresorptive therapy is provided to these patients. The objective of this study was to assess the frequency of bone fractures after heart transplantation, considering previous comorbidities, immunosuppressive therapy, and osteoprotective treatment. Methods. From 1993 to 2005, 443 consecutive heart transplant recipients were followed for the occurrence of bone fractures, immunosuppressive therapy, clinical conditions, and antiresorptive treatment. Results. There were 41 fractures in 34 patients (7.6%, group I). The remainder of patients formed group II. Fractures commonly involved the lumbar spine. Postmenopausal women had more fractures than other patients (20.6% vs 7.8%, P ⫽ .02). When the initial immunosuppressive regimen included tacrolimus, fractures did not happen (P ⫽ .01, vs other regimens). Osteoprotective therapy was administered to 91.2% of patients in group I and 79% in group II (P ⫽ .08). Mean interval from transplantation to the first fracture was 1131.5 days. Overweight patients had a 61.8% incidence of fracture. Conclusions. Our series showed a low frequency of bone fractures. Postmenopausal women and overweight patients had more fractures. An initial immunosuppressive regimen using tacrolimus was associated with lower fracture rates.
C
ARDIAC TRANSPLANTATION is a good therapeutic option for end-stage heart failure. However, bone loss and bone fractures remain important morbidities in these patients, affecting up to 44% of recipients.1 The loss in bone mass density is well known to occur in a dramatic manner during the first year posttransplantation.2– 4 Many patients have a poor bone density prior to transplantation because of the use of loop diuretics and impaired general condition. After transplantation, the use of immunosuppressive agents, such as steroids and cyclosporine, has deleterious effects on bone turnover. Various combinations of vitamins, hormones, and mineral supplements have been employed to palliate this situation. Newer immunosuppressive drugs with fewer effects on bone metabolism have also been introduced. We conducted a study to analyze the frequency of bone fractures among our population of heart recipients, considering clinical and epidemiological variables before and after heart transplantation (HT) while paying special attention to
the immunosuppressive regimens and the use of osteoprotective therapy. PATIENTS AND METHODS This clinical study consisted of a cohort of 443 consecutive HT recipients engrafted from January 1993 to December 2005. We From the Fuenlabrada University Hospital, Cardiología, Fuenlabrada, Spain (M.L., J.J.A.), and Complexo Hospitalario Universitario Juan Canalejo, Área del Corazón, A Coruña, Spain (M.G.C.L., M.J.P.M., J.G.d.L., R.M.R., P.P.E., G.C., R.R., C.N.L., A.C.B.). This study was funded by the Ministerio de Sanidad y Consumo: Instituto de Salud Carlos III, Red Temática de Investigación Cardiovascular (RECAVA) (Spanish Ministry of Health and Consumption: Carlos III Health Institute, The Thematic Network of Cardiovascular Research – RECAVA). Address reprint requests to Marı´a Luaces Méndez, Fuenlabrada University Hospital, Cardiologı´a, Camino del Molino, 2. 28942 Fuenlabrada, Spain. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.07.063
Transplantation Proceedings, 39, 2393–2396 (2007)
2393
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LUACES MENDEZ, CRESPO LEIRO, PANIAGUA MARTIN ET AL
retrospectively analyzed data collected in medical records. Of the entire cohort, 372 patients (83.9%) were men and 71 (16.1%) were women. The mean follow-up was 1755 ⫾ 1365 days. Group (gr) I included patients who experienced fracture after transplantation, and II encompassed those who did not suffer bone fracture.
Assessment of Bone Fractures Bone fractures were detected through imaging techniques (X rays, magnetic resonance imaging). Routine surveillance imaging tests included annual chest X ray. Lumbar spine radiographs were not scheduled. Fractures were diagnosed through clinical complaints or as incident fractures on imaging performed for other reasons. Image tests were analyzed by skeletal radiologists.
Immunosuppressive Therapy
Table 2. Osteoprotective Therapy in 354 Heart Transplant Recipients Frequency
Vitamin D Calcium Biphosphonates Calcitonin
n
%
346 353 284 13
97.7 99.9 80.2 3.7
RESULTS
There were 41 fractures in 34 patients, which represented 7.6% of our HT patients. Twenty-seven suffered 1 fracture; 6 patients had 2 fractures; and 1 patient fractured 4 times.
The immunosuppressive therapy was modified over time. All patients were administered induction treatment. From 1991 to 2000, the immunosuppressive protocol consisted of OKT3 (5 mg/d, mean 4 doses). In 2000, we began to use basiliximab (20 mg on HT day and 20 mg on day 4 post-HT). From 2002 on, OKT3 was completely replaced by basiliximab. Regarding basal immunosuppression, from 1991 to April 1998 it consisted of cyclosporine (CsA), azathioprine (AZA), and prednisone. In 1995, mycophenolate mofetil (MMF) was introduced as a rescue treatment replacing AZA, and from 1998, AZA was also substituted for MMF as basal immunosuppression. From November 1998, tacrolimus was used as a rescue treatment or because of adverse effects of CsA. Episodes of acute rejection (endomyocardial biopsy with grade ⱖ3A or 2R ISHLT) were treated with methylprednisone (250 mg to 1 g bolus per day) for 3 days.
Pretransplantation Conditions
Osteoprotective Therapy
Posttransplantation Period
After transplantation, supplements of calcium (1000 mg/d) and vitamin D (calcifediol 0.266 mg for 15 days) were recommended for all patients. In cases of renal insufficiency, the doses were halved. Biphosphonates were initially administered as 4 cycles of etidronate (400 mg/d) followed by 45 days without taking the drug. Later etidronate was substituted by risedronate, which is currently administered 35 mg weekly.
Osteprotective therapy was provided to 79.9% of patients (Table 2). Among them, 97.7% received vitamin D; 99.9% calcium; 80.2% biphosphonates; and 3.7% calcitonin (8 men and 5 women).
Table 1. Epidemiological Characteristics and Comorbidities in 443 Heart Transplantations
Age ⬎65 y Men Women Urgent transplantation Cause of transplantation Dilated myocardiopathy Ischemic heart disease Diabetes Renal insufficiency Previous fractures Postmenopausal Pretransplantation overweight Pretransplantation obesity Osteoprotective therapy
Fractures (Gr I, n ⫽ 34)
No Fractures (Gr II, n ⫽ 409)
1 (2.9%) 25 (73.5%) 9 (26.5%) 7 (20.6%)
40 (9.8%) 347 (84.8%) 62 (15.2%) 59 (14.5%)
.18 .08
11 (32.4%) 17 (50.0%) 3 (8.8%) 1 (3%) 1 (2.9%) 7 (20.6%) 18 (52.9%) 1 (3.8%) 31 (91.2%)
174 (42.5%) 173 (42.3%) 85 (20.7%) 44 (11.2%) 9 (2.2%) 32 (7.8%) 197 (48.1%) 28 (14.8%) 323 (79%)
.93
P
.33
.71 .14 .78 .02 .12 .08
Baseline characteristics are presented in Table 1. When transplanted, the mean age in gr I was 57.12 ⫾ 9.26 vs 55.03 ⫾ 10.43 years in gr II (P ⫽ .25). Fractures were more common in women than in men (26.5% vs 15.2%, P ⫽ .08). The percentage of fractures among postmenopausal women was markedly higher compared with other patients (20.6% gr I vs 7.8% gr II, P ⫽ .02). Considered separately, these women also sustained more fractures than fertile women (77.8% vs 22.2%, respectively, P ⫽ .17). Most transplants were needed because of ischemic heart disease or idiopathic cardiomyopathy. There were no differences between the groups in terms of preexistent comorbidities: diabetes, renal insufficiency, or previous fractures.
Immunosuppressive Regimens
Immunosuppression included steroids, CsA, and an antimetabolite (either AZA or MMF) in 91.4% of cases. The remaining 8.6% were based on steroids, tacrolimus, and an antimetabolite. None of the patients receiving tacrolimus as calcineurin inhibitor fractured (P ⫽ .01; Table 3). The immunosuppressive regimen was changed in 324 patients. Again, fractures were less common when the immunosuppressive regimen included tacrolimus instead of CsA (P ⫽ .09, data not shown). Table 3. Initial Immunosuppressive Regimens
CsA ⫹ Aza ⫹ Pred CsA ⫹ MMF ⫹ Pred FK ⫹ MMF ⫹ Pred FK ⫹ Aza ⫹ Pred
Fractures (Gr I, n ⫽ 34)
No Fractures (Gr II, n ⫽ 360)
29 (85.3%) 5 (14.7%) 0 0
202 (56.1%) 135 (37.5%) 17 (4.7%) 6 (1.7%)
P
.01
CsA, cyclosporine; Aza, azathioprine; Pred, prednisone; MMF, mycophenolate mofetil; FK, tacrolimus.
BONE FRACTURES AFTER HT
2395
Table 4. Distribution of Fractures
Vertebral Hip Ribs Other (long bones) Total
First Fracture
Second Fracture
Further
Total
19 6 5 5 35
0 2 2 1 5
0 1 0 0 1
19 9 7 6 41
Bone Fractures
There were 41 fractures in 34 patients (7.6%). The mean interval from HT to the first fracture was 1131.5 ⫾ 1042 days (range, 92–3932 days; median, 591.5 days). Body mass index (BMI) when the fracture was diagnosed was ⬎25 kg/m2 in 70% of cases (61.8% at the moment of first fracture). Most were axial fractures: 28 involved the spine (6 lumbar, 5 dorsal, 1 cervical, 2 in multiple locations, and 5 unspecified). There were 9 hip fractures. Other locations included ribs (7 cases) and long bones (6 cases; table 4). The fracture was symptomatic in 30 of 41 episodes (73.1%). In other cases, the fracture was diagnosed by the radiologist on studies performed for other reasons. When the fracture was symptomatic, the mean interval from transplantation to the event was 813.22 ⫾ 763.58 days, whereas in incident fractures the mean time was 2359.42 ⫾ 1112.52 days (P ⬍ .001). Among patients who fractured, 91.2% were receiving antiresorptive treatment. In 5 cases, the fracture occurred before we implemented osteoprotective therapy. Clinical Outcomes
The fracture warranted surgical treatment (mainly at the expense of hip prostheses) in 10 cases (29.4%). In none of the cases did the fracture cause the death of the patient. DISCUSSION
Despite important advances in maintenance therapy, the loss of bone mass density (BMD) and bone fractures are still significant complications following HT. The 7.6% of patients sustaining fractures observed herein seemed lower compared with other series, namely, rates from 13.6% to 35%.2,5–7 Actually our rate reflected clinical practice and agreed with recent reports in the era of osteoprotective therapy,8 whereas in other series routine radiographs were performed to detect fractures. Bone turnover and metabolism are altered in recipients of organ transplants but the etiology and pathogenesis are only partially known. Osteopenia in HT recipients differs from that in other solid organ transplantations. As a general rule, HT patients do not experience long-term immobilization or severe impairment of renal function. Loop-diuretics, secondary hyperparathyroidism, and decreased activity may have a role in the osteopenia of patients with severe chronic heart failure.9 After transplantation the use of steroids impairs bone metabolism several ways. Not only in steroids
accelerate bone resorption but, importantly, they directly suppress osteoblastic activity and decrease their lifespan.10 Some studies have shown long-term recovery in BMD, suggesting the ability of the patient to overcome the effects of continued therapy with steroids.11 Other immunosuppressive agents have deleterious effects on bone metabolism. CsA, a calcineurin inhibitor, has dramatically improved survival of HT patients since its introduction in the 1980s. But this agent has been shown to reduce trabecular bone in a time and dose-dependent manner.12,13 An alternative to CsA is tacrolimus (FK 506), a calcineurin inhibitor that is 100-fold more potent than CsA in vitro. The role of tacrolimus in bone turnover remains controversial.14 Some studies in animals have shown a reduction in trabecular bone, although not as severe as what is induced by CsA. In a series of 7 patients, Stempfle et al15 detected significant reduction of BMD with tacrolimus. A striking finding in our study was the absence of fractures among the small number of patients with tacrolimus-based initial immunosuppressive regimens. This observation confirms other clinical series,16 suggesting potential advantage compared with CsA. Other immunosuppressive agents such as AZA, MMF, and newer agents like sirolimus appear to exert no effects on bone turnover.16,17,18 In any case, the individual role of each immunosuppressive agent is difficult to weigh, since they are administered in combination in clinical practice. Bone Turnover and Fractures
During the first posttransplantation year, bone loss is estimated in 7.3% at the lumbar spine and 10.5% at the femoral neck.3,7,19 This finding has been attributed to an excess of bone resorption, since biochemical markers such as urinary calcium, hydroxyproline, and deoxypyridinoline are increased. Nevertheless, biochemical markers of bone turnover do not predict the risk of bone loss20 and many patients fracture with normal BMD.2 In our population the mean interval was longer, probably due to the lack of systematic lumbar spine X-ray imaging. Several strategies seek to counterbalance the damage of immunosuppressive agents on bone loss. The role of antiresorptive therapy to reduce the risk of fracture is not definite.8,16 Supplements of calcium and vitamin D were effective in preventing fractures in one study.16 Initial studies showed increased BMD with fluoride in patients with established osteoporosis. Calcium and calcidiol contributed to ameliorate the bone loss and control secondary hyperparathyroidism.21 Other biphosphonates such as alendronate and a potent metabolite of vitamin D, calcitriol, have been studied recently.8 Calcitriol may protect against corticosteroid-induced bone loss by augmenting calcium absorption and stimulating osteoblasts. Although bone loss was less severe than in untreated patients, rates of fractures were not reduced. Clodronate, a second-generation biphosphonate, may be useful in patients with established bone loss after transplantation. Initial studies have shown avoidance of new fractures and recovery of bone mass.22
2396
The duration of osteoprotective therapy still needs to be determined. Studies with calcitriol suggest that treatment ought to be continued after 1 year to maintain BMD.23–25 The problem with calcitriol lies in its narrow therapeutic window. Hypercalciuria and hypercalcemia easily appear, forcing discontinuation of treatment. Biphosphonates exert long-lasting binding to bone after their administration. This beneficial effect should be cautiously considered, because further structural anomalies can evolve, leading to osteodystrophy. Further studies focused on this subject are needed. Female Gender and Fractures
The influence of female gender in fractures has not been properly assessed because women account for a low number of HT recipients (16.1% in our series). The excess risk in female recipients was observed by Shane et al.7 We undoubtedly agree that their lower BMD prior to transplantation predisposes them to a high rate of fractures, despite supplements with calcitonin. In our series, 3 of 5 women treated with calcitonin suffered fractures. BMI and Fractures
We observed a high prevalence of overweight among patients sustaining fractures. Increased body weight is a concern in transplant recipients; it is related to the use of steroids. The overload of body mass poses another risk to the reduced BMD. This clinical observation needs to be confirmed by specific anthropometric studies. In conclusion, our study showed that bone fractures after HT still occur in the era of antiresorptive therapies. Postmenopausal women displayed a higher frequency of fractures than other patients. We have observed that the small cohort of patients treated with tacrolimus had a low occurrence of fractures, but a larger series and longer follow-up are warranted before a definitive conclusion. Limitations of the Study
This study had several limitations. BMD by densitometry was not performed in all cases so data are not shown. Biochemical markers of bone turnover had not been routinely determined. The limited number of patients with fractures prevented detection of statistically significant differences. REFERENCES 1. 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) 50:347, 1999 2. Shane E, Rivas MC, Silverberg SJ, et al: Osteoporosis after cardiac transplantation. Am J Med 94:257, 1993 3. Shane E, Rivas M, McMahon DJ, et al: Bone loss and turnover after cardiac transplantation. J Clin Endocrinol Metab 82:1497, 1997
LUACES MENDEZ, CRESPO LEIRO, PANIAGUA MARTIN ET AL 4. Sambrook PN, Kelly PJ, Fontana D, et al: Mechanisms of rapid bone loss following cardiac transplantation. Osteoporos Int 4:273, 1994 5. Ramsey-Goldman R, Dunn JE, Dunlop DD, et al: Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res 14:456, 1999 6. Negri AL, Perrone S, Gallo R, et al: Osteoporosis following heart transplantation. Transplant Proc 28:3321, 1996 7. Shane E, Rivas M, Staron RB, et al: Fracture after cardiac transplantation: a prospective longitudinal study. J Clin Endocrinol Metab 81:1740, 1996 8. Shane E, Addesso V, Namerow PB, et al: Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 350:767, 2004 9. Lee AH, Mull RL, Keenan GF, et al: Osteoporosis and bone morbidity in cardiac transplant recipients. Am J Med 96:35, 1994 10. Dempster DW: Bone histomorphometry in glucocorticoidinduced osteoporosis. J Bone Miner Res 4:137, 1989 11. Kapetanakis EI, Antonopoulos AS, Antoniou TA, et al: Effect of long-term calcitonin administration on steroid-induced osteoporosis after cardiac transplantation. J Heart Lung Transplant 24:526, 2005 12. Epstein S: Post-transplantation bone disease: the role of immunosuppressive agents and the skeleton. J Bone Miner Res 11:1, 1996 13. Cvetkovic M, Mann GN, Romero DF, et al: The deleterious effects of long-term cyclosporine A, cyclosporine G, and FK506 on bone mineral metabolism in vivo. Transplantation 57:1231, 1994 14. Inoue T, Kawamura I, Matsuo M, et al: Lesser reduction in bone mineral density by the immunosuppressant, FK506, compared with cyclosporine in rats. Transplantation 70:774, 2000 15. Stempfle HU, Werner C, Echtler S, et al: Rapid trabecular bone loss after cardiac transplantation using FK506 (tacrolimus)based immunosuppression. Transplant Proc 30:1132, 1998 16. 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 357:342, 2001 17. Dissanayake IR, Goodman GR, Bowman AR, et al: Mycophenolate mofetil: a promising new immunosuppressant that does not cause bone loss in the rat. Transplantation 65:275, 1998 18. Romero DF, Buchinsky FJ, Rucinski B, et al: Rapamycin: a bone sparing immunosuppressant? J Bone Miner Res 10:760, 1995 19. Sambrook PN, Kelly PJ, Keogh AM, et al: Bone loss after heart transplantation: a prospective study. J Heart Lung Transplant 13:116, 1994 20. 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 67:116, 2000 21. Meys E, Terreaux-Duvert F, Beaume-Six T, et al: Bone loss after cardiac transplantation: effects of calcium, calcidiol and monofluorophosphate. Osteoporos Int 3:322, 1993 22. Ippoliti G, Pellegrini C, Campana C, et al: Clodronate treatment of established bone loss in cardiac recipients: a randomized study. Transplantation 75:330, 2003 23. Sambrook P, Henderson NK, Keogh A, et al: Effect of calcitriol on bone loss after cardiac or lung transplantation. J Bone Miner Res 15:1818, 2000 24. 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 16:565, 2001 25. Cohen A, Addesso V, McMahon DJ, et al: Discontinuing antiresorptive therapy one year after cardiac transplantation: effect on bone density and bone turnover. Transplantation 81:686, 2006
C
ARDIAC TRANSPLANTATION is a good therapeutic option for end-stage heart failure. However, bone loss and bone fractures remain important morbidities in these patients, affecting up to 44% of recipients.1 The loss in bone mass density is well known to occur in a dramatic manner during the first year posttransplantation.2– 4 Many patients have a poor bone density prior to transplantation because of the use of loop diuretics and impaired general condition. After transplantation, the use of immunosuppressive agents, such as steroids and cyclosporine, has deleterious effects on bone turnover. Various combinations of vitamins, hormones, and mineral supplements have been employed to palliate this situation. Newer immunosuppressive drugs with fewer effects on bone metabolism have also been introduced. We conducted a study to analyze the frequency of bone fractures among our population of heart recipients, considering clinical and epidemiological variables before and after heart transplantation (HT) while paying special attention to
the immunosuppressive regimens and the use of osteoprotective therapy. PATIENTS AND METHODS This clinical study consisted of a cohort of 443 consecutive HT recipients engrafted from January 1993 to December 2005. We From the Fuenlabrada University Hospital, Cardiología, Fuenlabrada, Spain (M.L., J.J.A.), and Complexo Hospitalario Universitario Juan Canalejo, Área del Corazón, A Coruña, Spain (M.G.C.L., M.J.P.M., J.G.d.L., R.M.R., P.P.E., G.C., R.R., C.N.L., A.C.B.). This study was funded by the Ministerio de Sanidad y Consumo: Instituto de Salud Carlos III, Red Temática de Investigación Cardiovascular (RECAVA) (Spanish Ministry of Health and Consumption: Carlos III Health Institute, The Thematic Network of Cardiovascular Research – RECAVA). Address reprint requests to Marı´a Luaces Méndez, Fuenlabrada University Hospital, Cardiologı´a, Camino del Molino, 2. 28942 Fuenlabrada, Spain. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.07.063
Transplantation Proceedings, 39, 2393–2396 (2007)
2393
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LUACES MENDEZ, CRESPO LEIRO, PANIAGUA MARTIN ET AL
retrospectively analyzed data collected in medical records. Of the entire cohort, 372 patients (83.9%) were men and 71 (16.1%) were women. The mean follow-up was 1755 ⫾ 1365 days. Group (gr) I included patients who experienced fracture after transplantation, and II encompassed those who did not suffer bone fracture.
Assessment of Bone Fractures Bone fractures were detected through imaging techniques (X rays, magnetic resonance imaging). Routine surveillance imaging tests included annual chest X ray. Lumbar spine radiographs were not scheduled. Fractures were diagnosed through clinical complaints or as incident fractures on imaging performed for other reasons. Image tests were analyzed by skeletal radiologists.
Immunosuppressive Therapy
Table 2. Osteoprotective Therapy in 354 Heart Transplant Recipients Frequency
Vitamin D Calcium Biphosphonates Calcitonin
n
%
346 353 284 13
97.7 99.9 80.2 3.7
RESULTS
There were 41 fractures in 34 patients, which represented 7.6% of our HT patients. Twenty-seven suffered 1 fracture; 6 patients had 2 fractures; and 1 patient fractured 4 times.
The immunosuppressive therapy was modified over time. All patients were administered induction treatment. From 1991 to 2000, the immunosuppressive protocol consisted of OKT3 (5 mg/d, mean 4 doses). In 2000, we began to use basiliximab (20 mg on HT day and 20 mg on day 4 post-HT). From 2002 on, OKT3 was completely replaced by basiliximab. Regarding basal immunosuppression, from 1991 to April 1998 it consisted of cyclosporine (CsA), azathioprine (AZA), and prednisone. In 1995, mycophenolate mofetil (MMF) was introduced as a rescue treatment replacing AZA, and from 1998, AZA was also substituted for MMF as basal immunosuppression. From November 1998, tacrolimus was used as a rescue treatment or because of adverse effects of CsA. Episodes of acute rejection (endomyocardial biopsy with grade ⱖ3A or 2R ISHLT) were treated with methylprednisone (250 mg to 1 g bolus per day) for 3 days.
Pretransplantation Conditions
Osteoprotective Therapy
Posttransplantation Period
After transplantation, supplements of calcium (1000 mg/d) and vitamin D (calcifediol 0.266 mg for 15 days) were recommended for all patients. In cases of renal insufficiency, the doses were halved. Biphosphonates were initially administered as 4 cycles of etidronate (400 mg/d) followed by 45 days without taking the drug. Later etidronate was substituted by risedronate, which is currently administered 35 mg weekly.
Osteprotective therapy was provided to 79.9% of patients (Table 2). Among them, 97.7% received vitamin D; 99.9% calcium; 80.2% biphosphonates; and 3.7% calcitonin (8 men and 5 women).
Table 1. Epidemiological Characteristics and Comorbidities in 443 Heart Transplantations
Age ⬎65 y Men Women Urgent transplantation Cause of transplantation Dilated myocardiopathy Ischemic heart disease Diabetes Renal insufficiency Previous fractures Postmenopausal Pretransplantation overweight Pretransplantation obesity Osteoprotective therapy
Fractures (Gr I, n ⫽ 34)
No Fractures (Gr II, n ⫽ 409)
1 (2.9%) 25 (73.5%) 9 (26.5%) 7 (20.6%)
40 (9.8%) 347 (84.8%) 62 (15.2%) 59 (14.5%)
.18 .08
11 (32.4%) 17 (50.0%) 3 (8.8%) 1 (3%) 1 (2.9%) 7 (20.6%) 18 (52.9%) 1 (3.8%) 31 (91.2%)
174 (42.5%) 173 (42.3%) 85 (20.7%) 44 (11.2%) 9 (2.2%) 32 (7.8%) 197 (48.1%) 28 (14.8%) 323 (79%)
.93
P
.33
.71 .14 .78 .02 .12 .08
Baseline characteristics are presented in Table 1. When transplanted, the mean age in gr I was 57.12 ⫾ 9.26 vs 55.03 ⫾ 10.43 years in gr II (P ⫽ .25). Fractures were more common in women than in men (26.5% vs 15.2%, P ⫽ .08). The percentage of fractures among postmenopausal women was markedly higher compared with other patients (20.6% gr I vs 7.8% gr II, P ⫽ .02). Considered separately, these women also sustained more fractures than fertile women (77.8% vs 22.2%, respectively, P ⫽ .17). Most transplants were needed because of ischemic heart disease or idiopathic cardiomyopathy. There were no differences between the groups in terms of preexistent comorbidities: diabetes, renal insufficiency, or previous fractures.
Immunosuppressive Regimens
Immunosuppression included steroids, CsA, and an antimetabolite (either AZA or MMF) in 91.4% of cases. The remaining 8.6% were based on steroids, tacrolimus, and an antimetabolite. None of the patients receiving tacrolimus as calcineurin inhibitor fractured (P ⫽ .01; Table 3). The immunosuppressive regimen was changed in 324 patients. Again, fractures were less common when the immunosuppressive regimen included tacrolimus instead of CsA (P ⫽ .09, data not shown). Table 3. Initial Immunosuppressive Regimens
CsA ⫹ Aza ⫹ Pred CsA ⫹ MMF ⫹ Pred FK ⫹ MMF ⫹ Pred FK ⫹ Aza ⫹ Pred
Fractures (Gr I, n ⫽ 34)
No Fractures (Gr II, n ⫽ 360)
29 (85.3%) 5 (14.7%) 0 0
202 (56.1%) 135 (37.5%) 17 (4.7%) 6 (1.7%)
P
.01
CsA, cyclosporine; Aza, azathioprine; Pred, prednisone; MMF, mycophenolate mofetil; FK, tacrolimus.
BONE FRACTURES AFTER HT
2395
Table 4. Distribution of Fractures
Vertebral Hip Ribs Other (long bones) Total
First Fracture
Second Fracture
Further
Total
19 6 5 5 35
0 2 2 1 5
0 1 0 0 1
19 9 7 6 41
Bone Fractures
There were 41 fractures in 34 patients (7.6%). The mean interval from HT to the first fracture was 1131.5 ⫾ 1042 days (range, 92–3932 days; median, 591.5 days). Body mass index (BMI) when the fracture was diagnosed was ⬎25 kg/m2 in 70% of cases (61.8% at the moment of first fracture). Most were axial fractures: 28 involved the spine (6 lumbar, 5 dorsal, 1 cervical, 2 in multiple locations, and 5 unspecified). There were 9 hip fractures. Other locations included ribs (7 cases) and long bones (6 cases; table 4). The fracture was symptomatic in 30 of 41 episodes (73.1%). In other cases, the fracture was diagnosed by the radiologist on studies performed for other reasons. When the fracture was symptomatic, the mean interval from transplantation to the event was 813.22 ⫾ 763.58 days, whereas in incident fractures the mean time was 2359.42 ⫾ 1112.52 days (P ⬍ .001). Among patients who fractured, 91.2% were receiving antiresorptive treatment. In 5 cases, the fracture occurred before we implemented osteoprotective therapy. Clinical Outcomes
The fracture warranted surgical treatment (mainly at the expense of hip prostheses) in 10 cases (29.4%). In none of the cases did the fracture cause the death of the patient. DISCUSSION
Despite important advances in maintenance therapy, the loss of bone mass density (BMD) and bone fractures are still significant complications following HT. The 7.6% of patients sustaining fractures observed herein seemed lower compared with other series, namely, rates from 13.6% to 35%.2,5–7 Actually our rate reflected clinical practice and agreed with recent reports in the era of osteoprotective therapy,8 whereas in other series routine radiographs were performed to detect fractures. Bone turnover and metabolism are altered in recipients of organ transplants but the etiology and pathogenesis are only partially known. Osteopenia in HT recipients differs from that in other solid organ transplantations. As a general rule, HT patients do not experience long-term immobilization or severe impairment of renal function. Loop-diuretics, secondary hyperparathyroidism, and decreased activity may have a role in the osteopenia of patients with severe chronic heart failure.9 After transplantation the use of steroids impairs bone metabolism several ways. Not only in steroids
accelerate bone resorption but, importantly, they directly suppress osteoblastic activity and decrease their lifespan.10 Some studies have shown long-term recovery in BMD, suggesting the ability of the patient to overcome the effects of continued therapy with steroids.11 Other immunosuppressive agents have deleterious effects on bone metabolism. CsA, a calcineurin inhibitor, has dramatically improved survival of HT patients since its introduction in the 1980s. But this agent has been shown to reduce trabecular bone in a time and dose-dependent manner.12,13 An alternative to CsA is tacrolimus (FK 506), a calcineurin inhibitor that is 100-fold more potent than CsA in vitro. The role of tacrolimus in bone turnover remains controversial.14 Some studies in animals have shown a reduction in trabecular bone, although not as severe as what is induced by CsA. In a series of 7 patients, Stempfle et al15 detected significant reduction of BMD with tacrolimus. A striking finding in our study was the absence of fractures among the small number of patients with tacrolimus-based initial immunosuppressive regimens. This observation confirms other clinical series,16 suggesting potential advantage compared with CsA. Other immunosuppressive agents such as AZA, MMF, and newer agents like sirolimus appear to exert no effects on bone turnover.16,17,18 In any case, the individual role of each immunosuppressive agent is difficult to weigh, since they are administered in combination in clinical practice. Bone Turnover and Fractures
During the first posttransplantation year, bone loss is estimated in 7.3% at the lumbar spine and 10.5% at the femoral neck.3,7,19 This finding has been attributed to an excess of bone resorption, since biochemical markers such as urinary calcium, hydroxyproline, and deoxypyridinoline are increased. Nevertheless, biochemical markers of bone turnover do not predict the risk of bone loss20 and many patients fracture with normal BMD.2 In our population the mean interval was longer, probably due to the lack of systematic lumbar spine X-ray imaging. Several strategies seek to counterbalance the damage of immunosuppressive agents on bone loss. The role of antiresorptive therapy to reduce the risk of fracture is not definite.8,16 Supplements of calcium and vitamin D were effective in preventing fractures in one study.16 Initial studies showed increased BMD with fluoride in patients with established osteoporosis. Calcium and calcidiol contributed to ameliorate the bone loss and control secondary hyperparathyroidism.21 Other biphosphonates such as alendronate and a potent metabolite of vitamin D, calcitriol, have been studied recently.8 Calcitriol may protect against corticosteroid-induced bone loss by augmenting calcium absorption and stimulating osteoblasts. Although bone loss was less severe than in untreated patients, rates of fractures were not reduced. Clodronate, a second-generation biphosphonate, may be useful in patients with established bone loss after transplantation. Initial studies have shown avoidance of new fractures and recovery of bone mass.22
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The duration of osteoprotective therapy still needs to be determined. Studies with calcitriol suggest that treatment ought to be continued after 1 year to maintain BMD.23–25 The problem with calcitriol lies in its narrow therapeutic window. Hypercalciuria and hypercalcemia easily appear, forcing discontinuation of treatment. Biphosphonates exert long-lasting binding to bone after their administration. This beneficial effect should be cautiously considered, because further structural anomalies can evolve, leading to osteodystrophy. Further studies focused on this subject are needed. Female Gender and Fractures
The influence of female gender in fractures has not been properly assessed because women account for a low number of HT recipients (16.1% in our series). The excess risk in female recipients was observed by Shane et al.7 We undoubtedly agree that their lower BMD prior to transplantation predisposes them to a high rate of fractures, despite supplements with calcitonin. In our series, 3 of 5 women treated with calcitonin suffered fractures. BMI and Fractures
We observed a high prevalence of overweight among patients sustaining fractures. Increased body weight is a concern in transplant recipients; it is related to the use of steroids. The overload of body mass poses another risk to the reduced BMD. This clinical observation needs to be confirmed by specific anthropometric studies. In conclusion, our study showed that bone fractures after HT still occur in the era of antiresorptive therapies. Postmenopausal women displayed a higher frequency of fractures than other patients. We have observed that the small cohort of patients treated with tacrolimus had a low occurrence of fractures, but a larger series and longer follow-up are warranted before a definitive conclusion. Limitations of the Study
This study had several limitations. BMD by densitometry was not performed in all cases so data are not shown. Biochemical markers of bone turnover had not been routinely determined. The limited number of patients with fractures prevented detection of statistically significant differences. REFERENCES 1. 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) 50:347, 1999 2. Shane E, Rivas MC, Silverberg SJ, et al: Osteoporosis after cardiac transplantation. Am J Med 94:257, 1993 3. Shane E, Rivas M, McMahon DJ, et al: Bone loss and turnover after cardiac transplantation. J Clin Endocrinol Metab 82:1497, 1997
LUACES MENDEZ, CRESPO LEIRO, PANIAGUA MARTIN ET AL 4. Sambrook PN, Kelly PJ, Fontana D, et al: Mechanisms of rapid bone loss following cardiac transplantation. Osteoporos Int 4:273, 1994 5. Ramsey-Goldman R, Dunn JE, Dunlop DD, et al: Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res 14:456, 1999 6. Negri AL, Perrone S, Gallo R, et al: Osteoporosis following heart transplantation. Transplant Proc 28:3321, 1996 7. Shane E, Rivas M, Staron RB, et al: Fracture after cardiac transplantation: a prospective longitudinal study. J Clin Endocrinol Metab 81:1740, 1996 8. Shane E, Addesso V, Namerow PB, et al: Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 350:767, 2004 9. Lee AH, Mull RL, Keenan GF, et al: Osteoporosis and bone morbidity in cardiac transplant recipients. Am J Med 96:35, 1994 10. Dempster DW: Bone histomorphometry in glucocorticoidinduced osteoporosis. J Bone Miner Res 4:137, 1989 11. Kapetanakis EI, Antonopoulos AS, Antoniou TA, et al: Effect of long-term calcitonin administration on steroid-induced osteoporosis after cardiac transplantation. J Heart Lung Transplant 24:526, 2005 12. Epstein S: Post-transplantation bone disease: the role of immunosuppressive agents and the skeleton. J Bone Miner Res 11:1, 1996 13. Cvetkovic M, Mann GN, Romero DF, et al: The deleterious effects of long-term cyclosporine A, cyclosporine G, and FK506 on bone mineral metabolism in vivo. Transplantation 57:1231, 1994 14. Inoue T, Kawamura I, Matsuo M, et al: Lesser reduction in bone mineral density by the immunosuppressant, FK506, compared with cyclosporine in rats. Transplantation 70:774, 2000 15. Stempfle HU, Werner C, Echtler S, et al: Rapid trabecular bone loss after cardiac transplantation using FK506 (tacrolimus)based immunosuppression. Transplant Proc 30:1132, 1998 16. 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 357:342, 2001 17. Dissanayake IR, Goodman GR, Bowman AR, et al: Mycophenolate mofetil: a promising new immunosuppressant that does not cause bone loss in the rat. Transplantation 65:275, 1998 18. Romero DF, Buchinsky FJ, Rucinski B, et al: Rapamycin: a bone sparing immunosuppressant? J Bone Miner Res 10:760, 1995 19. Sambrook PN, Kelly PJ, Keogh AM, et al: Bone loss after heart transplantation: a prospective study. J Heart Lung Transplant 13:116, 1994 20. 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 67:116, 2000 21. Meys E, Terreaux-Duvert F, Beaume-Six T, et al: Bone loss after cardiac transplantation: effects of calcium, calcidiol and monofluorophosphate. Osteoporos Int 3:322, 1993 22. Ippoliti G, Pellegrini C, Campana C, et al: Clodronate treatment of established bone loss in cardiac recipients: a randomized study. Transplantation 75:330, 2003 23. Sambrook P, Henderson NK, Keogh A, et al: Effect of calcitriol on bone loss after cardiac or lung transplantation. J Bone Miner Res 15:1818, 2000 24. 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 16:565, 2001 25. Cohen A, Addesso V, McMahon DJ, et al: Discontinuing antiresorptive therapy one year after cardiac transplantation: effect on bone density and bone turnover. Transplantation 81:686, 2006