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Efficacy and Safety of Bisphosphonates for Osteoporosis or Osteopenia in Cardiac Transplant Patients: A Meta-Analysis
Efficacy and Safety of Bisphosphonates for Osteoporosis or Osteopenia in Cardiac Transplant Patients: A Meta-Analysis J. Zhaoa, C. Wangb, and Z. Hua,* a Department of Orthopedic Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; and bDepartment of Clinical Laboratory, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
ABSTRACT Background. After cardiac transplantation (CTP), the loss of bone mass is accelerated and there is an increased risk for bone fractures. Bisphosphonates are commonly used for preventing loss of bone mass after CTP. However, no systematic evaluation of the treatment efficacy of bisphosphonates after CTP has been reported. The aim of this metaanalysis was to assess the effectiveness and safety of bisphosphonates for osteoporosis or osteopenia after CTP. Methods. An electronic database search including Medline, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies up to March 2015. We included randomized controlled trials (RCTs) and nonrandomized prospective comparative studies that were concerned with bisphosphonates for osteoporosis after CTP. Statistical analyses were conducted with the use of Review Manager 5.1.6. Results. Three RCTs and 3 nonrandomized prospective studies involving 425 participants were included. Eight and 12 months after CTP, compared with the control groups, vertebral bone mineral density (BMD) in patients treated with bisphosphonates was w0.06 g/cm2 higher than in control patients (weighted mean difference [WMD], 0.06 g/cm2; 95% CI, 0.03e0.08 g/cm2; P < .0001). The loss of femoral neck BMD was 0.03 g/cm2 lower in patients treated with bisphosphonates than in control patients; however, this difference was not statistically significant (WMD, 0.03 g/cm2; 95% CI, 0e0.05 g/cm2; P ¼ .06). No bisphosphonate treatmenterelated serious adverse reactions were found in the patients. Conclusions. In the early stage after CTP, bisphosphonates effectively reduced the loss of bone mass, especially in vertebral BMD.
L
OSS of bone mineral density (BMD) is a serious complication after cardiac transplantation (CTP). Many studies have demonstrated that BMD is reduced rapidly during the 1st year after transplantation, with the prevalence of fractures ranging from 22% to 35% and the incidence for vertebral fractures ranging from 14% to 36% [1e5]. Multiple factors contribute to the loss of BMD, in which immunosuppressive therapy has a main role in inducing bone loss. Steroids lead to rapid bone loss within the 1st 3- 6 months of its use [6]. Trabecular bone is usually affected earlier and more severely than cortical bone [7]. Fracture risk is also increased rapidly during the 1st few months of therapy. The precise effect of cyclosporine on the human skeleton remains controversial [8e10], but its immunosuppressive effects probably increases bone turnover
[4,11,12]. The lack of weight-bearing activity, hypogonadism, nutritional deficits, and extensive use of loop diuretics may be additional factors that cause rapid bone loss after CTP [13e17]. Osteoclast recruitment, differentiation, and activity are inhibited by bisphosphonates, which also potently inhibit bone resorption [18]. They are approved for the treatment of osteoporosis in postmenopausal women and lead to significant improvement in bone mass [19e22] and a reduction in subsequent fractures [23,24]. Several clinical trials have
*Address correspondence to Zhenming Hu, 1 You yi Rd Yu zhong District 400016, Chongqing, People’s Republic of China. E-mail: [email protected]
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0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.10.049
Transplantation Proceedings, 47, 2957e2964 (2015)
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been conducted to evaluate the effectiveness and adverse effects of bisphosphonate therapy for osteoporosis or osteopenia in CTP. However, those studies have been limited by the small number of patients and/or single-center design. Therefore, we performed the present meta-analysis to estimate the efficacy and safety of bisphosphonate therapy for osteoporosis or osteopenia in CTP. MATERIALS AND METHODS Literature Search Electronic databases (ie, Medline, Embase, and the Cochrane Central Register of Controlled Trials), which were last updated on December 28, 2014, were searched without limit by 2 independent investigators. The key words used included: (alendronate OR pamidronate OR etidronate OR zoledronate OR clodronate OR bisphosphonate) AND (“heart transplantation” or “cardiac transplantation” or “heart graft”). A manual search of the reference lists in the selected articles was performed to identify any additional trials. Unpublished data in abstracts from scientific meetings held over the past few years were identified by means of a manual search. Authors of relevant papers were contacted for additional information if required.
ZHAO, WANG, AND HU and compared that with the control group with the use of the following formula [31]: Mcombined ¼
N1 M1 þ N2 M2 N1 þ N2
SDcombined ¼ vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u N1 N2 2 u uðN1 1ÞSD21 þ ðN2 1ÞSD22 þ M 1 þ M 22 2M1 M2 t N1 þ N2 N1 þ N2 1 For the continuous outcome results, we calculated the BMD changes from baseline at the lumbar spine and femoral neck with the use of the mean and SD change, and mean differences and 95% confidence intervals (CIs) were used to compare the effect of bisphosphonates with the control group (P values of 05 were considered to be significant). We also assessed heterogeneity by means of calculating the I2, with a value >50% considered to indicate substantial heterogeneity. The Mantel-Haenszel fixed-effect model was used. Initially, where a substantial heterogeneity existed, a random-effects model was used to combine the results. Sensitivity analysis was conducted to determine the source of heterogeneity by removing 1 study from the analysis.
Study Selection We included randomized controlled trials (RCTs) and nonrandomized prospective comparative studies that used bisphosphonate in CTP either alone or in combination with calcium and/or vitamin D supplementation, with the control groups receiving a placebo or no treatment either alone or in combination with the same supplementation. We selected studies in which participants were >18 years old and received immunosuppression after cardiac transplantation of glucocorticoids and cyclosporine, as well as bisphosphonates in any dose. Studies were excluded if the effect of bisphosphonate in CTP was investigated after discontinuing antiresorptive therapy.
Data Extraction and Management Two independent investigators (Cai Wang and Zhenming Hu) extracted the data, and disagreements were resolved by a 3rd independent author. Many studies have reported that rapid bone loss happened during the 1st year after transplantation, especially during the 1st 6 months [25e29]. We therefore chose to examine the change in BMD within the 1st year after cardiac transplantation. We collected data regarding the incidence of new fractures and adverse events, if provided. Two authors (Cai Wang and Zhenming Hu) conducted a quality assessment of each study with the use of the Downs and Black checklist [30], which assesses descriptions of randomized and nonrandomized studies by means of 27 questions to obtain a total score ranging from 0 to 32. If the total score was 0e14, the study was classified as poor quality; if the total score was 15e32, the study was classified as better quality. Statistical analyses were conducted with the use of Review Manager 5.3 (Nordic Cochrane Center, Cochrane Collaboration). We extracted intention-to-treat data from trials whenever possible. If the mean BMD was not reported in the trial, we extrapolated it from the accompanying graphs with the use of Engauge Digitizer 5.1. If the trial only contained SEMs, we converted the SEMs to SDs. For 1 trial, which had 2 different bisphosphonates as intervention, we combined the data from 2 different bisphosphonates
RESULTS Literature Search
The literature search with the use of the terms mentioned above revealed 202 potentially relevant studies. By screening titles and abstracts, 91 duplicate or nonrelevant articles were excluded. On more detailed review, 2 retrospective studies were excluded [32,33] and another study that analyzed results after discontinuation of antiresorptive therapy was discarded (Fig 1). Therefore, 3 RCTs [25,34,35] and 3 nonrandomized prospective studies [27,36,37] met our inclusion criteria. There were 208 patients in the bisphosphonate groups and 217 patients in the control groups. The risk of bias assessment according to the Downs
Fig 1. Search strategy.
EFFICACY AND SAFETY OF BISPHOSPHONATES
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Table 1. Assessment of Risk Bias of Included Studies According to Downs and Black Checklist Downs and Black Checklist
Q1: Aim clearly described Q2: Outcomes clearly described Q3: Characteristics of the patients clearly described Q4: Interventions clearly described Q5: Principal confounders clearly described Q6: Main findings clearly described Q7: Random variability for main outcomes provided Q8: Adverse events reported Q9: Loss to follow-up described Q10: Actual P values reported Q11: Subjects asked to participate representative of the entire population Q12: Subjects prepared to participate representative of the entire population Q13: Staff representative of patient’s environments Q14: Attempt to blind participants Q15: Attempt to blind assessors Q16: Data-dredging results stated clearly Q17: Analysis adjusted for length of follow-up Q18: Appropriate statistics Q19: Reliable compliance Q20: Accurate outcome measures Q21: Same population Q22: Participants recruited at the same time Q23: Randomized Q24: Adequate allocation concealment Q25: Adequate adjustment for confounders Q26: Loss to follow-up reported Q27: Power calculation
Braith 2003 [34]
Shane 2004 [36]
Fahrleitner-Pammer 2009 [25]
Ippoliti 2003 [35]
Krieg 2001 [27]
Gilfraguas 2012 [37]
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes No UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes No No UD
UD
UD
UD
UD
UD
UD
UD No No Yes Yes Yes UD yes Yes Yes Yes No No Yes
UD No UD Yes Yes Yes UD Yes Yes Yes NO No No Yes
UD Yes Yes Yes Yes Yes UD Yes Yes Yes Yes Yes Yes Yes
UD Yes No Yes Yes Yes UD Yes Yes Yes Yes No No Yes
UD No No Yes Yes Yes UD Yes No Yes No No No Yes
UD No No Yes Yes Yes UD Yes No Yes No No No UD
Abbreviation: UD, unable to determine.
and Black checklist of the included studies is presented in Table 1. Study Characteristics
As presented in Table 2, Except for Ippoliti et al’s study (administered at 6 months after CTP), bisphosphonates were administrated within 2 months after CTP, and in Shane and Fahrleitner-Pammer’s study, bisphosphonates were administrated within a day after CTP. The follow-up of patients lasted from 8 months to 3 years after CTP. One study used intravenous bisphosphonates, and the other 5 used oral bisphosphonates after CTP. Among these 6 studies, 2 of them used alendronate, 1 used clodronate, 1 used pamidronate, and 1 used either alendronate or etidronate. Four studies supplemented calcium and vitamin D in both experimental and control groups. One study supplemented only calcium, and 1 gave a placebo to the control group. All patients received cyclosporine treatment after CTP. Dosages of cyclosporine were adjusted according to the blood concentration of cyclosporine. All studies used the standard definition of osteoporosis and decrease of bone mass from the World Health Organization and used dualenergy X-ray absorptiometry to measure the BMD. All studies reported the lumbar spine BMD, 5 studies reported the femoral neck BMD, 2 studies reported trochanter
BMD, 1 study reported total hip and entire femur BMD, 1 study reported forearm BMD, and 1 study reported total body BMD. Five of the studies provided the incidence of bone fractures. Effect of Interventions
Mean Percentage Change in Lumbar Spine BMD. Six studies reported the changes in lumbar spine BMD before and after bisphosphonate treatment (Fig 2). Test of heterogeneity between studies demonstrated that I2 ¼ 28% and P ¼ .23, suggesting that all studies were homogeneous, and therefore a fixed-effect model was used. The results of mean percentage changes in lumbar spine BMD after bisphosphonate treatment demonstrated statistical significance (weighted mean difference [WMD], 0.06 g/cm2; 95% CI, 0.03e0.08 g/cm2; P < .0001), indicating that bisphosphonate treatment after CTP (8e12 mo) increased the lumbar spine BMD by 0.06 g/cm2 compared with the control groups. Due to the presence of the 3 prospective controlled studies, we used a subgroup analysis, and no significant heterogeneity was found between the bisphosphonate treatment groups and the control groups (I2 ¼ 42.8%; P ¼ .19). Mean Percentage Change in Femoral Neck BMD. Five studies reported the changes in femoral neck BMD before
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Table 2. Characteristics of the Six Included Trials
Study
Timing of Initiation of Bisphosphonates after CTP
Duration (mo)
Bisphosphonate Group
Control Group
Oral alendronate, 10 mg/d
No
Patient/ Control (n)
Mean Age
Immunosuppression
outcomes mesure
8/9
56(5)/54(6)
Cyclosporine, prednisone and azathioprine
Total body BMD.Areal BMD:femur neck and L2-3BMD Areal BMD: femur neck, total hip and lumbar BMD; Biochemical markers: NTx, PTH Fracture Areal BMD:femur neck, trochanter and lumbar BMD; Biochemical markers:
Brait et al 2003, [34]
2 mo
6
Shane et al, 2004 [36]
1 mo
12
Oral alendronate, 10 mg/d þ Calcium, 945 mg/ calcium, 945 mg/d, and d, and vitamin vitamin D, 1,000 IU/d D, 1,000 IU/d
74/27
54(11)/56(8)
Cyclosporine, prednisone and methylprednisolone
within 24 h
12
IV ibandronate, 2 mg every 3 mo þ calcium, 500 mg/d, and vitamin D, 400 IU/d
17/18
45.3(6)/43.4(8)
Cyclosporine, prednisone and methylprednisolone
6 mo
12
Oral clodronate, 1,600 mg/ d þ calcium, 2,000 mg/d
32/32
50(17)/51(12)
Cyclosporine, prednisone, azathioprine
Areal BMD:lumbar and forearm BMD
36
Oral pamidronate, 60 mg every 3 mo þ calcium, 1,000 mg/d, and vitamin D, 1,000 IU/d Oral alendronate, 10 mg/d, or etidronate, 400 mg/d, for 2 wk every 3 mo þ calcium, 1,000 mg/d, and vitamin D, 800 IU/d
Placebo þ calcium, 500 mg/d, and vitamin D, 400 IU/d Placebo þ calcium, 2,000 mg/d Calcium, 1,000 mg/d, and vitamin D, 1,000 IU/d Calcium, 1,000 mg/d, and vitamin D, 800 IU/d
11/17
46(4)/51(3)
Cyclosporine, azathioprine, prednisone or methylprednisolone
Areal BMD:femur neck, trochanter and lumbar BMD
78/102
51(12)/52(9)
Cyclosporine, prednisone and methylprednisolone
Areal BMD:femur neck, entire femur and lumbar BMD
FahrleitnerPammer et al, 2009 [25]
Ippoliti et al, 2003 [35] Krieg et al, 2001 [27]
Gilfraguas et al, 2012 [37]
At the time of transplantation
Within 15 d
24
ZHAO, WANG, AND HU
EFFICACY AND SAFETY OF BISPHOSPHONATES
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Fig 2. Forest plot of comparison 1: mean percentage change in lumbar BMD, bisphosphonates versus placebo or no intervention.
and after bisphosphonate treatment (Fig 3). A test of heterogeneity between studies demonstrated that I2 ¼ 0 and P ¼ .72, suggesting that all studies were homogeneous, and therefore a fixed-effect model was used. Compared with the control group, bisphosphonate treatment reduced the loss in femur neck BMD by 0.03 g/cm2 in the patients after CTP (WMD, 0.03 g/cm2; 95% CI, 00.05 g/cm2), but it was not statistically significant (P ¼ .06). No significant heterogeneity was found with the use of subgroup analysis to compare the prospective controlled studies and randomized control studies (I2 ¼ 0%; P ¼ .36). Bone Fractures and Adverse Effects
Five of the studies provided the incidence of bone fractures. However, given that nonvertebral fractures are less fatal than
vertebral fractures, 1 study reported the incidence of vertebral fractures but not the incidence of limb fractures after CTP. Another study described only the incidence of clinical bone fractures. The inconsistent end point evaluations of the different studies made proper assessment of the incidence of bone fractures difficult. The following summarizes the incidence of bone fractures as presented in Table 3. In all the studies, no bisphosphonate treatmenterelated loss to follow-up or serious adverse effects were reported. The study by Ippoliti et al showed that oral clodronate caused nausea and epigastric discomfort (22% of the patients) but was not serious. These patients did not quit the study because of the above symptoms, which eventually disappeared with prolonged oral clodronate treatment. Bisphosphonate treatment did not increase the rejection rate after CTP.
Fig 3. Forest plot of comparison 2: mean percentage change in femoral neck BMD, bisphosphonates versus placebo or no intervention.
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ZHAO, WANG, AND HU Table 3. Incidence of Fractures Study
Bisphosphonate Group
Control Group
Duration (mo)
Shane et al, 2004 [36] FahrleitnerPammer et al, 2009 [25] Ippoliti et al, 2003 [35] Krieg et al, 2001 [27] Gilfraguas et al, 2012 [37]
4 pts with 8 vertebral fractures and 4 pts with nonvertebral fractures 2 pts with vertebral fractures
3 pts with 8 vertebral fractures
12
9 pts with vertebral fractures
12
No clinical fractures
2 pts with vertebral fractures and 1 pt with hip fracture No clinical fractures
12
16 pts with vertebral fractures
24
No clinical fractures 3 pts (6.7%) in alendronate group and 3 pts (9.1%) in etidronate group with vertebral fractures
36
Abbreviation: pts, patients.
DISCUSSION
To study the role of bisphosphonates on preventing bone mass decline after CTP, this study included 3 RCTs and 3 prospective studies. Some researchers may question the reliability of prospective studies, but owing to the limited number of CTP patients, the number of participants in randomized studies is relatively few. The prospective studies included many more participants; if we excluded this group of patients, it would affect the external validity of our findings. In this study, we scored the included literature with the use of the Downs and Black checklist. All studies included in this meta-analysis had relatively good quality. In addition, we used subgroup analysis for different types of studies and confirmed no significant heterogeneity between the prospective studies and the randomized studies. In the present meta-analysis, no significant heterogeneity was found among the included studies, suggesting that all of the studies used fixed-effect models for analysis. Metaanalysis showed that bisphosphonate treatment within a year after CTP could significantly increase vertebral BMD by w0.06 g/cm2 compared with a placebo or control group. This finding was consistent with the meta-analysis by Mitterbauer et al [38] in vertebral BMD after kidney transplantation and bisphosphonate treatment. In the metaanalysis by Kasturi et al [39], which analyzed effects 1 year after liver transplantation, bisphosphonate treatment was associated with an increase of 0.03 g/cm2 in vertebral BMD. In the present meta-analysis, although no statistically significant difference was found in femoral neck BMD between the bisphosphonate treatment and control groups, the loss of femoral neck BMD was 0.03 g/cm2 lower in the bisphosphonate treatment groups than in the control groups. Similarly, the meta-analyses by Mitterbauer et al [38] and Kasturi et al [39] found that the losses of femoral neck BMD were, respectively, 0.05 g/cm2 (P ¼ .067) and 0.02 g/cm2 (P ¼ .19) lower in the bisphosphonate treatment groups than in control groups. Immunosuppression is an important cause of osteoporosis after CTP. Moreover, the administration dosage and timing of immunosuppressants are significantly associated with the degree of osteoporosis [40]. Among the 6 studies included here, the administration of immunosuppressants
was analyzed in both treatment and control groups. Except for the study by Gilfraguas et al, where the etidronate group used a higher dosage of prednisone than the control group at 12 months after CTP, the administration of immunosuppressants in the treatment and the control groups was rather consistent. These facilitated the analysis of the impact of bisphosphates on BMD. Importantly, the comparison between etidronate and alendronate in Gilfraguas et al’s study showed that alendronate improved vertebral and femoral neck BMDs significantly better than etidronate a year after CTP. However, the dosage of prednisone administration in the etidronate group was significantly higher. Although the present analysis merged the etidronate and alendronate group, more studies using different bisphosphates should be analyzed to confirm the treatment efficacy on improving BMDs after CTP. As a commonly used antiosteoporosis drug, the common side effects of bisphosphonates mainly affect the function of the gastrointestinal tract and kidneys. Among the 6 studies, no bisphosphonate treatmenterelated serious adverse side effects were reported. Prevention of bone fractures was an important criterion for assessing the treatment effects of osteoporosis. Fahrleitner-Pammer et al reported the incidence of morphometric vertebral fractures. At a year after CTP, the incidence of bone fractures in the ibandronate treatment group was 13%, whereas the incidence of bone fractures in the control group was 53%, with a statistically significant difference between the 2 groups (P ¼ .02). Ibandronate treatment significantly reduced the incidence of morphometric vertebral fractures compared with the control group. Similarly, in the study by Ippoliti et al, more vertebral and nonvertebral bone fractures were found in the control group than in the treatment group. However, in the studies by Shane et al and Gilfraguas et al, no significant difference in bone fracture numbers was found among different types of bone fractures. The study by Krieg et al showed that no new incidence of clinical fractures was found in either the pamidronate treatment group or the control group. Nevertheless, owing to the inconsistent assessments of bone fractures and the differences in bone fracture sites, we did not conduct a meta-analysis of bone fractures. In addition, the number of patients undergoing CTP was
EFFICACY AND SAFETY OF BISPHOSPHONATES
smaller, and the evaluation of drug intervention required a larger sample size to assess the treatment efficacy on bone fractures. Therefore, long-term follow-up studies are needed for such evaluation. The present meta-analysis represented only published literature and did not involve unpublished studies, which is one of the inadequacies. Moreover, the number of included studies was relatively small, and with a limited sample size in each study. Owing to the small number of studies, we evaluated only the overall treatment effect of bisphosphonates. However, different formulations of bisphosphonates may have different treatment efficacies, which possibly caused statistical bias and further affected our findings in this study. In short, the existing data show that bisphosphonates reduced the loss of bone mass and significantly increased vertebral BMD a year after CTP. Although the reduction of femoral neck BMD in the bisphosphonate treatment group was lower than the control group, the current data did not demonstrate a statistically significant difference. Therefore, many consistent outcomes will be needed for the evaluation of the efficacy of bisphosphonate on preventing bone fractures. Studies of different types of bisphosphonates and treatment durations should also be considered.
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2964 [33] Yong G, Hayes H, O’Driscoll G. Strategy of aggressive steroid weaning and routine alendronate therapy to reduce bone loss after cardiac transplantation. Transplant Proc 2007;39: 3340e3. [34] Braith RW, Magyari PM, Fulton MN, et al. Resistance exercise training and alendronate reverse glucocorticoid-induced osteoporosis in heart transplant recipients. J Heart Lung Transplant 2003;22:1082e90. [35] Ippoliti G, Pellegrini C, Campana C, et al. Clodronate treatment of established bone loss in cardiac recipients: a randomized study. Transplantation 2003;75:330e4. [36] 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;350:767e76.
ZHAO, WANG, AND HU [37] Gilfraguas L, Guadalix S, Martinez G, et al. Bone loss after heart transplant: effect of alendronate, etidronate, calcitonin, and calcium plus vitamin D3. Prog Transplant 2012;l22:3. [38] Mitterbauer C, Schwarz C, Haas M. Effects of bisphosphonates on bone loss in the first year after renal transplantation-a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 2006;21:75e81. [39] Kasturi KS, Chennareddygari S, Mummadi RR. Effect of bisphosphonates on bone mineral density in liver transplant patients: a meta-analysis and systematic review of randomized controlled trials. Transpl Int 2010;23:200e7. [40] Pazianas M, Cooper C, Ebetino FH, Russell RG. Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. Ther Clin Risk Manag 2010;6:325e43.
ABSTRACT Background. After cardiac transplantation (CTP), the loss of bone mass is accelerated and there is an increased risk for bone fractures. Bisphosphonates are commonly used for preventing loss of bone mass after CTP. However, no systematic evaluation of the treatment efficacy of bisphosphonates after CTP has been reported. The aim of this metaanalysis was to assess the effectiveness and safety of bisphosphonates for osteoporosis or osteopenia after CTP. Methods. An electronic database search including Medline, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies up to March 2015. We included randomized controlled trials (RCTs) and nonrandomized prospective comparative studies that were concerned with bisphosphonates for osteoporosis after CTP. Statistical analyses were conducted with the use of Review Manager 5.1.6. Results. Three RCTs and 3 nonrandomized prospective studies involving 425 participants were included. Eight and 12 months after CTP, compared with the control groups, vertebral bone mineral density (BMD) in patients treated with bisphosphonates was w0.06 g/cm2 higher than in control patients (weighted mean difference [WMD], 0.06 g/cm2; 95% CI, 0.03e0.08 g/cm2; P < .0001). The loss of femoral neck BMD was 0.03 g/cm2 lower in patients treated with bisphosphonates than in control patients; however, this difference was not statistically significant (WMD, 0.03 g/cm2; 95% CI, 0e0.05 g/cm2; P ¼ .06). No bisphosphonate treatmenterelated serious adverse reactions were found in the patients. Conclusions. In the early stage after CTP, bisphosphonates effectively reduced the loss of bone mass, especially in vertebral BMD.
L
OSS of bone mineral density (BMD) is a serious complication after cardiac transplantation (CTP). Many studies have demonstrated that BMD is reduced rapidly during the 1st year after transplantation, with the prevalence of fractures ranging from 22% to 35% and the incidence for vertebral fractures ranging from 14% to 36% [1e5]. Multiple factors contribute to the loss of BMD, in which immunosuppressive therapy has a main role in inducing bone loss. Steroids lead to rapid bone loss within the 1st 3- 6 months of its use [6]. Trabecular bone is usually affected earlier and more severely than cortical bone [7]. Fracture risk is also increased rapidly during the 1st few months of therapy. The precise effect of cyclosporine on the human skeleton remains controversial [8e10], but its immunosuppressive effects probably increases bone turnover
[4,11,12]. The lack of weight-bearing activity, hypogonadism, nutritional deficits, and extensive use of loop diuretics may be additional factors that cause rapid bone loss after CTP [13e17]. Osteoclast recruitment, differentiation, and activity are inhibited by bisphosphonates, which also potently inhibit bone resorption [18]. They are approved for the treatment of osteoporosis in postmenopausal women and lead to significant improvement in bone mass [19e22] and a reduction in subsequent fractures [23,24]. Several clinical trials have
*Address correspondence to Zhenming Hu, 1 You yi Rd Yu zhong District 400016, Chongqing, People’s Republic of China. E-mail: [email protected]
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0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.10.049
Transplantation Proceedings, 47, 2957e2964 (2015)
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been conducted to evaluate the effectiveness and adverse effects of bisphosphonate therapy for osteoporosis or osteopenia in CTP. However, those studies have been limited by the small number of patients and/or single-center design. Therefore, we performed the present meta-analysis to estimate the efficacy and safety of bisphosphonate therapy for osteoporosis or osteopenia in CTP. MATERIALS AND METHODS Literature Search Electronic databases (ie, Medline, Embase, and the Cochrane Central Register of Controlled Trials), which were last updated on December 28, 2014, were searched without limit by 2 independent investigators. The key words used included: (alendronate OR pamidronate OR etidronate OR zoledronate OR clodronate OR bisphosphonate) AND (“heart transplantation” or “cardiac transplantation” or “heart graft”). A manual search of the reference lists in the selected articles was performed to identify any additional trials. Unpublished data in abstracts from scientific meetings held over the past few years were identified by means of a manual search. Authors of relevant papers were contacted for additional information if required.
ZHAO, WANG, AND HU and compared that with the control group with the use of the following formula [31]: Mcombined ¼
N1 M1 þ N2 M2 N1 þ N2
SDcombined ¼ vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u N1 N2 2 u uðN1 1ÞSD21 þ ðN2 1ÞSD22 þ M 1 þ M 22 2M1 M2 t N1 þ N2 N1 þ N2 1 For the continuous outcome results, we calculated the BMD changes from baseline at the lumbar spine and femoral neck with the use of the mean and SD change, and mean differences and 95% confidence intervals (CIs) were used to compare the effect of bisphosphonates with the control group (P values of 05 were considered to be significant). We also assessed heterogeneity by means of calculating the I2, with a value >50% considered to indicate substantial heterogeneity. The Mantel-Haenszel fixed-effect model was used. Initially, where a substantial heterogeneity existed, a random-effects model was used to combine the results. Sensitivity analysis was conducted to determine the source of heterogeneity by removing 1 study from the analysis.
Study Selection We included randomized controlled trials (RCTs) and nonrandomized prospective comparative studies that used bisphosphonate in CTP either alone or in combination with calcium and/or vitamin D supplementation, with the control groups receiving a placebo or no treatment either alone or in combination with the same supplementation. We selected studies in which participants were >18 years old and received immunosuppression after cardiac transplantation of glucocorticoids and cyclosporine, as well as bisphosphonates in any dose. Studies were excluded if the effect of bisphosphonate in CTP was investigated after discontinuing antiresorptive therapy.
Data Extraction and Management Two independent investigators (Cai Wang and Zhenming Hu) extracted the data, and disagreements were resolved by a 3rd independent author. Many studies have reported that rapid bone loss happened during the 1st year after transplantation, especially during the 1st 6 months [25e29]. We therefore chose to examine the change in BMD within the 1st year after cardiac transplantation. We collected data regarding the incidence of new fractures and adverse events, if provided. Two authors (Cai Wang and Zhenming Hu) conducted a quality assessment of each study with the use of the Downs and Black checklist [30], which assesses descriptions of randomized and nonrandomized studies by means of 27 questions to obtain a total score ranging from 0 to 32. If the total score was 0e14, the study was classified as poor quality; if the total score was 15e32, the study was classified as better quality. Statistical analyses were conducted with the use of Review Manager 5.3 (Nordic Cochrane Center, Cochrane Collaboration). We extracted intention-to-treat data from trials whenever possible. If the mean BMD was not reported in the trial, we extrapolated it from the accompanying graphs with the use of Engauge Digitizer 5.1. If the trial only contained SEMs, we converted the SEMs to SDs. For 1 trial, which had 2 different bisphosphonates as intervention, we combined the data from 2 different bisphosphonates
RESULTS Literature Search
The literature search with the use of the terms mentioned above revealed 202 potentially relevant studies. By screening titles and abstracts, 91 duplicate or nonrelevant articles were excluded. On more detailed review, 2 retrospective studies were excluded [32,33] and another study that analyzed results after discontinuation of antiresorptive therapy was discarded (Fig 1). Therefore, 3 RCTs [25,34,35] and 3 nonrandomized prospective studies [27,36,37] met our inclusion criteria. There were 208 patients in the bisphosphonate groups and 217 patients in the control groups. The risk of bias assessment according to the Downs
Fig 1. Search strategy.
EFFICACY AND SAFETY OF BISPHOSPHONATES
2959
Table 1. Assessment of Risk Bias of Included Studies According to Downs and Black Checklist Downs and Black Checklist
Q1: Aim clearly described Q2: Outcomes clearly described Q3: Characteristics of the patients clearly described Q4: Interventions clearly described Q5: Principal confounders clearly described Q6: Main findings clearly described Q7: Random variability for main outcomes provided Q8: Adverse events reported Q9: Loss to follow-up described Q10: Actual P values reported Q11: Subjects asked to participate representative of the entire population Q12: Subjects prepared to participate representative of the entire population Q13: Staff representative of patient’s environments Q14: Attempt to blind participants Q15: Attempt to blind assessors Q16: Data-dredging results stated clearly Q17: Analysis adjusted for length of follow-up Q18: Appropriate statistics Q19: Reliable compliance Q20: Accurate outcome measures Q21: Same population Q22: Participants recruited at the same time Q23: Randomized Q24: Adequate allocation concealment Q25: Adequate adjustment for confounders Q26: Loss to follow-up reported Q27: Power calculation
Braith 2003 [34]
Shane 2004 [36]
Fahrleitner-Pammer 2009 [25]
Ippoliti 2003 [35]
Krieg 2001 [27]
Gilfraguas 2012 [37]
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes No UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes Yes Yes UD
Yes Yes Yes Yes Partially Yes Yes Yes No No UD
UD
UD
UD
UD
UD
UD
UD No No Yes Yes Yes UD yes Yes Yes Yes No No Yes
UD No UD Yes Yes Yes UD Yes Yes Yes NO No No Yes
UD Yes Yes Yes Yes Yes UD Yes Yes Yes Yes Yes Yes Yes
UD Yes No Yes Yes Yes UD Yes Yes Yes Yes No No Yes
UD No No Yes Yes Yes UD Yes No Yes No No No Yes
UD No No Yes Yes Yes UD Yes No Yes No No No UD
Abbreviation: UD, unable to determine.
and Black checklist of the included studies is presented in Table 1. Study Characteristics
As presented in Table 2, Except for Ippoliti et al’s study (administered at 6 months after CTP), bisphosphonates were administrated within 2 months after CTP, and in Shane and Fahrleitner-Pammer’s study, bisphosphonates were administrated within a day after CTP. The follow-up of patients lasted from 8 months to 3 years after CTP. One study used intravenous bisphosphonates, and the other 5 used oral bisphosphonates after CTP. Among these 6 studies, 2 of them used alendronate, 1 used clodronate, 1 used pamidronate, and 1 used either alendronate or etidronate. Four studies supplemented calcium and vitamin D in both experimental and control groups. One study supplemented only calcium, and 1 gave a placebo to the control group. All patients received cyclosporine treatment after CTP. Dosages of cyclosporine were adjusted according to the blood concentration of cyclosporine. All studies used the standard definition of osteoporosis and decrease of bone mass from the World Health Organization and used dualenergy X-ray absorptiometry to measure the BMD. All studies reported the lumbar spine BMD, 5 studies reported the femoral neck BMD, 2 studies reported trochanter
BMD, 1 study reported total hip and entire femur BMD, 1 study reported forearm BMD, and 1 study reported total body BMD. Five of the studies provided the incidence of bone fractures. Effect of Interventions
Mean Percentage Change in Lumbar Spine BMD. Six studies reported the changes in lumbar spine BMD before and after bisphosphonate treatment (Fig 2). Test of heterogeneity between studies demonstrated that I2 ¼ 28% and P ¼ .23, suggesting that all studies were homogeneous, and therefore a fixed-effect model was used. The results of mean percentage changes in lumbar spine BMD after bisphosphonate treatment demonstrated statistical significance (weighted mean difference [WMD], 0.06 g/cm2; 95% CI, 0.03e0.08 g/cm2; P < .0001), indicating that bisphosphonate treatment after CTP (8e12 mo) increased the lumbar spine BMD by 0.06 g/cm2 compared with the control groups. Due to the presence of the 3 prospective controlled studies, we used a subgroup analysis, and no significant heterogeneity was found between the bisphosphonate treatment groups and the control groups (I2 ¼ 42.8%; P ¼ .19). Mean Percentage Change in Femoral Neck BMD. Five studies reported the changes in femoral neck BMD before
2960
Table 2. Characteristics of the Six Included Trials
Study
Timing of Initiation of Bisphosphonates after CTP
Duration (mo)
Bisphosphonate Group
Control Group
Oral alendronate, 10 mg/d
No
Patient/ Control (n)
Mean Age
Immunosuppression
outcomes mesure
8/9
56(5)/54(6)
Cyclosporine, prednisone and azathioprine
Total body BMD.Areal BMD:femur neck and L2-3BMD Areal BMD: femur neck, total hip and lumbar BMD; Biochemical markers: NTx, PTH Fracture Areal BMD:femur neck, trochanter and lumbar BMD; Biochemical markers:
Brait et al 2003, [34]
2 mo
6
Shane et al, 2004 [36]
1 mo
12
Oral alendronate, 10 mg/d þ Calcium, 945 mg/ calcium, 945 mg/d, and d, and vitamin vitamin D, 1,000 IU/d D, 1,000 IU/d
74/27
54(11)/56(8)
Cyclosporine, prednisone and methylprednisolone
within 24 h
12
IV ibandronate, 2 mg every 3 mo þ calcium, 500 mg/d, and vitamin D, 400 IU/d
17/18
45.3(6)/43.4(8)
Cyclosporine, prednisone and methylprednisolone
6 mo
12
Oral clodronate, 1,600 mg/ d þ calcium, 2,000 mg/d
32/32
50(17)/51(12)
Cyclosporine, prednisone, azathioprine
Areal BMD:lumbar and forearm BMD
36
Oral pamidronate, 60 mg every 3 mo þ calcium, 1,000 mg/d, and vitamin D, 1,000 IU/d Oral alendronate, 10 mg/d, or etidronate, 400 mg/d, for 2 wk every 3 mo þ calcium, 1,000 mg/d, and vitamin D, 800 IU/d
Placebo þ calcium, 500 mg/d, and vitamin D, 400 IU/d Placebo þ calcium, 2,000 mg/d Calcium, 1,000 mg/d, and vitamin D, 1,000 IU/d Calcium, 1,000 mg/d, and vitamin D, 800 IU/d
11/17
46(4)/51(3)
Cyclosporine, azathioprine, prednisone or methylprednisolone
Areal BMD:femur neck, trochanter and lumbar BMD
78/102
51(12)/52(9)
Cyclosporine, prednisone and methylprednisolone
Areal BMD:femur neck, entire femur and lumbar BMD
FahrleitnerPammer et al, 2009 [25]
Ippoliti et al, 2003 [35] Krieg et al, 2001 [27]
Gilfraguas et al, 2012 [37]
At the time of transplantation
Within 15 d
24
ZHAO, WANG, AND HU
EFFICACY AND SAFETY OF BISPHOSPHONATES
2961
Fig 2. Forest plot of comparison 1: mean percentage change in lumbar BMD, bisphosphonates versus placebo or no intervention.
and after bisphosphonate treatment (Fig 3). A test of heterogeneity between studies demonstrated that I2 ¼ 0 and P ¼ .72, suggesting that all studies were homogeneous, and therefore a fixed-effect model was used. Compared with the control group, bisphosphonate treatment reduced the loss in femur neck BMD by 0.03 g/cm2 in the patients after CTP (WMD, 0.03 g/cm2; 95% CI, 00.05 g/cm2), but it was not statistically significant (P ¼ .06). No significant heterogeneity was found with the use of subgroup analysis to compare the prospective controlled studies and randomized control studies (I2 ¼ 0%; P ¼ .36). Bone Fractures and Adverse Effects
Five of the studies provided the incidence of bone fractures. However, given that nonvertebral fractures are less fatal than
vertebral fractures, 1 study reported the incidence of vertebral fractures but not the incidence of limb fractures after CTP. Another study described only the incidence of clinical bone fractures. The inconsistent end point evaluations of the different studies made proper assessment of the incidence of bone fractures difficult. The following summarizes the incidence of bone fractures as presented in Table 3. In all the studies, no bisphosphonate treatmenterelated loss to follow-up or serious adverse effects were reported. The study by Ippoliti et al showed that oral clodronate caused nausea and epigastric discomfort (22% of the patients) but was not serious. These patients did not quit the study because of the above symptoms, which eventually disappeared with prolonged oral clodronate treatment. Bisphosphonate treatment did not increase the rejection rate after CTP.
Fig 3. Forest plot of comparison 2: mean percentage change in femoral neck BMD, bisphosphonates versus placebo or no intervention.
2962
ZHAO, WANG, AND HU Table 3. Incidence of Fractures Study
Bisphosphonate Group
Control Group
Duration (mo)
Shane et al, 2004 [36] FahrleitnerPammer et al, 2009 [25] Ippoliti et al, 2003 [35] Krieg et al, 2001 [27] Gilfraguas et al, 2012 [37]
4 pts with 8 vertebral fractures and 4 pts with nonvertebral fractures 2 pts with vertebral fractures
3 pts with 8 vertebral fractures
12
9 pts with vertebral fractures
12
No clinical fractures
2 pts with vertebral fractures and 1 pt with hip fracture No clinical fractures
12
16 pts with vertebral fractures
24
No clinical fractures 3 pts (6.7%) in alendronate group and 3 pts (9.1%) in etidronate group with vertebral fractures
36
Abbreviation: pts, patients.
DISCUSSION
To study the role of bisphosphonates on preventing bone mass decline after CTP, this study included 3 RCTs and 3 prospective studies. Some researchers may question the reliability of prospective studies, but owing to the limited number of CTP patients, the number of participants in randomized studies is relatively few. The prospective studies included many more participants; if we excluded this group of patients, it would affect the external validity of our findings. In this study, we scored the included literature with the use of the Downs and Black checklist. All studies included in this meta-analysis had relatively good quality. In addition, we used subgroup analysis for different types of studies and confirmed no significant heterogeneity between the prospective studies and the randomized studies. In the present meta-analysis, no significant heterogeneity was found among the included studies, suggesting that all of the studies used fixed-effect models for analysis. Metaanalysis showed that bisphosphonate treatment within a year after CTP could significantly increase vertebral BMD by w0.06 g/cm2 compared with a placebo or control group. This finding was consistent with the meta-analysis by Mitterbauer et al [38] in vertebral BMD after kidney transplantation and bisphosphonate treatment. In the metaanalysis by Kasturi et al [39], which analyzed effects 1 year after liver transplantation, bisphosphonate treatment was associated with an increase of 0.03 g/cm2 in vertebral BMD. In the present meta-analysis, although no statistically significant difference was found in femoral neck BMD between the bisphosphonate treatment and control groups, the loss of femoral neck BMD was 0.03 g/cm2 lower in the bisphosphonate treatment groups than in the control groups. Similarly, the meta-analyses by Mitterbauer et al [38] and Kasturi et al [39] found that the losses of femoral neck BMD were, respectively, 0.05 g/cm2 (P ¼ .067) and 0.02 g/cm2 (P ¼ .19) lower in the bisphosphonate treatment groups than in control groups. Immunosuppression is an important cause of osteoporosis after CTP. Moreover, the administration dosage and timing of immunosuppressants are significantly associated with the degree of osteoporosis [40]. Among the 6 studies included here, the administration of immunosuppressants
was analyzed in both treatment and control groups. Except for the study by Gilfraguas et al, where the etidronate group used a higher dosage of prednisone than the control group at 12 months after CTP, the administration of immunosuppressants in the treatment and the control groups was rather consistent. These facilitated the analysis of the impact of bisphosphates on BMD. Importantly, the comparison between etidronate and alendronate in Gilfraguas et al’s study showed that alendronate improved vertebral and femoral neck BMDs significantly better than etidronate a year after CTP. However, the dosage of prednisone administration in the etidronate group was significantly higher. Although the present analysis merged the etidronate and alendronate group, more studies using different bisphosphates should be analyzed to confirm the treatment efficacy on improving BMDs after CTP. As a commonly used antiosteoporosis drug, the common side effects of bisphosphonates mainly affect the function of the gastrointestinal tract and kidneys. Among the 6 studies, no bisphosphonate treatmenterelated serious adverse side effects were reported. Prevention of bone fractures was an important criterion for assessing the treatment effects of osteoporosis. Fahrleitner-Pammer et al reported the incidence of morphometric vertebral fractures. At a year after CTP, the incidence of bone fractures in the ibandronate treatment group was 13%, whereas the incidence of bone fractures in the control group was 53%, with a statistically significant difference between the 2 groups (P ¼ .02). Ibandronate treatment significantly reduced the incidence of morphometric vertebral fractures compared with the control group. Similarly, in the study by Ippoliti et al, more vertebral and nonvertebral bone fractures were found in the control group than in the treatment group. However, in the studies by Shane et al and Gilfraguas et al, no significant difference in bone fracture numbers was found among different types of bone fractures. The study by Krieg et al showed that no new incidence of clinical fractures was found in either the pamidronate treatment group or the control group. Nevertheless, owing to the inconsistent assessments of bone fractures and the differences in bone fracture sites, we did not conduct a meta-analysis of bone fractures. In addition, the number of patients undergoing CTP was
EFFICACY AND SAFETY OF BISPHOSPHONATES
smaller, and the evaluation of drug intervention required a larger sample size to assess the treatment efficacy on bone fractures. Therefore, long-term follow-up studies are needed for such evaluation. The present meta-analysis represented only published literature and did not involve unpublished studies, which is one of the inadequacies. Moreover, the number of included studies was relatively small, and with a limited sample size in each study. Owing to the small number of studies, we evaluated only the overall treatment effect of bisphosphonates. However, different formulations of bisphosphonates may have different treatment efficacies, which possibly caused statistical bias and further affected our findings in this study. In short, the existing data show that bisphosphonates reduced the loss of bone mass and significantly increased vertebral BMD a year after CTP. Although the reduction of femoral neck BMD in the bisphosphonate treatment group was lower than the control group, the current data did not demonstrate a statistically significant difference. Therefore, many consistent outcomes will be needed for the evaluation of the efficacy of bisphosphonate on preventing bone fractures. Studies of different types of bisphosphonates and treatment durations should also be considered.
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