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Efficacy and Safety of Different Bisphosphonates for Bone Loss Prevention in Kidney Transplant Recipients: A Network Meta-Analysis of Randomized Controlled Trials.

Byline: Yan. Yang, Shi. Qiu, Xi. Tang, Xin-Rui. Li, Ling-Hui. Deng, Qiang. Wei, Ping. Fu

Background: Mineral and bone disorder is one of the severe complications in kidney transplant recipients (KTRs). Previous studies showed that bisphosphonates had favorable effects on bone mineral density (BMD). We sought to compare different bisphosphonate regimens and rank their strategies. Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to April 01, 2017, for randomized controlled trials (RCTs) comparing bisphosphonate treatments in adult KTRs. The primary outcome was BMD change. We executed the tool recommended by the Cochrane Collaboration to evaluate the risk of bias. We performed pairwise meta-analyses using random effects models and network meta-analysis (NMA) using Bayesian models and assessed the quality of evidence. Results: A total of 21 RCTs (1332 participants) comparing 6 bisphosphonate regimens were included. All bisphosphonates showed a significantly increased percentage change in BMD at the lumbar spine compared to calcium except clodronate. Pamidronate with calcium and Vitamin D analogs showed improved BMD in comparison to clodronate with calcium (mean difference [MD], 9.84; 95% credibility interval [CrI], 1.06-19.70). The combination of calcium and Vitamin D analogs had a significantly lower influence than adding either pamidronate or alendronate (MD, 6.34; 95% CrI, 2.59-11.01 and MD, 6.16; 95% CrI, 0.54-13.24, respectively). In terms of percentage BMD change at the femoral neck, both pamidronate and ibandronate combined with calcium demonstrated a remarkable gain compared with calcium (MD, 7.02; 95% CrI, 0.30-13.29 and MD, 7.30; 95% CrI, 0.32-14.22, respectively). The combination of ibandronate with calcium displayed a significant increase in absolute BMD compared to any other treatments and was ranked best. Conclusions: Our NMA suggested that new-generation bisphosphonates such as ibandronate were more favorable in KTRs to improve BMD. However, the conclusion should be treated with caution due to indirect comparisons.

Introduction

Currently, an increasing number of people are suffering from chronic kidney disease that could progress to end-stage renal disease (ESRD). According to the latest United States Renal Data System Annual Data Report,[1] more than 660,000 Americans are afflicted with ESRD. Of these ESRD patients, over 193,000 underwent kidney transplantation (KT). Furthermore, mineral and bone disorders after KT increase fracture risk and contribute to cardiovascular disease, thereby impacting patient quality of life and long-term survival. Naylor et al .[2] reported that the 5-year cumulative incidence of fractures ranges from 0.85% to 27% after a successful KT. Furthermore, bone loss can also impose financial burdens by increasing patient morbidity and mortality.[3] Hence, prevention and treatment of bone loss are of great importance to the care of post-kidney transplant recipients (KTRs).

The etiology of bone disorders after KT is multifactorial with nearly all of KTRs suffering from preexisting bone disorders.[4] However, new bone disorders may also emerge following immunosuppressive treatment. Corticosteroid therapy, a main contributor, can decrease bone mass by inhibiting osteoblasts and stimulating osteoclasts.[5] Calcineurin inhibitors and patient immobility lead to bone loss as well.[6] Bisphosphonates are common antiresorptive agents employed against osteoporosis. The mechanism of action for bisphosphonates involves binding to bone mineral, which directly suppresses osteoclast activity and consequently reduces fracture risk.[7] Previous studies [8],[9] have shown that bisphosphonate therapy is an effective treatment for postmenopausal women with osteoporosis and glucocorticoid-induced osteoporosis. However, it remains unclear whether bisphosphonate treatment regimens are beneficial for KTRs because of the potential for nephrotoxicity and development of adynamic bone disease.[10]

Several meta-analyses [11],[12] have demonstrated that bisphosphonates have favorable effects on bone mineral density (BMD), but questionable effects on the risk of fracture. Moreover, it is unknown that which subclasses of bisphosphonates are more favorable in terms of prevention and treatment of post-KT bone disease. In addition, the results of these trials only compared all bisphosphonate treatments with either Vitamin D analogs or calcium (or both). Only a few head-to-head randomized trials of different bisphosphonates have been conducted.[13],[14] Therefore, it is difficult to evaluate the relative added value among various bisphosphonates classes. To obtain the estimates of relative treatment effects for all possible comparisons, we conducted a network meta-analysis (NMA). The present NMA seeks to systematically review the literature and determine the relative efficacy and safety of bisphosphonate therapies for treating bone loss after KT.

Methods

This systematic review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement extension for NMAs.[15]

Data sources and searches

To compare the tolerability and efficacy of different bisphosphonates in KTRs, a comprehensive search of the literature published up to April 01, 2017, was performed in the following databases: PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL). The reference lists of retrieved publications as well as relevant meta-analyses in the discipline were manually checked. We also searched international trial registries for trials in progress. The full-search parameters for each database are outlined in [Supplement 1 [SUPPORTING:1]]. Two independent investigators (YY and SQ) initially screened the citation titles and abstracts.

Study selection

Our preliminary search encompassed all RCTs comparing bisphosphonate-treated and control groups of KTRs. Studies that met the following criteria were finally involved: (1) trials were conducted in a homogenous group of de novo adult KTRs; (2) at least one of the interventions compared in the trial was bisphosphonate treatment and the protocol was listed clearly in the article; (3) the publication was a full-text original article; and (4) at least one trial outcome was of interest for our NMA. Citations were excluded for the following reasons: non-English text, review article, intervention, or study design. Studies accepting recipients of combined transplants including kidney, such as kidney-pancreas transplantation, were also excluded. If duplicate studies from identical authors were found, the reports were grouped together and only the publication with the most complete data was used. Any discrepancies in the study inclusion were resolved by consulting the senior authors (XT and QW).

Data extraction and quality assessment

The independent reviewers (YY and SQ) used a standardized form to extract information from each eligible study. Data regarding study-, patient-, and treatment-related characteristics and outcomes were extracted simultaneously. Attempts were made to obtain missing data from the first or corresponding authors of such studies. We assessed the validity of the NMA through a qualitative appraisal of study designs and methods. We executed the tool recommended by the Cochrane Collaboration to evaluate the risk of bias.[16]

Outcomes

The primary outcomes were the changes in BMD (percentage change and absolute change [in g/cm 2]) at the lumbar spine and the femoral neck after successful KTs. The secondary outcomes were overall fractures (both vertebral and nonvertebral fractures), all-cause mortality, graft loss, acute renal rejection, and adverse events. Only fractures that occurred after the subjects entered the study and during the reported follow-up time were used to calculate fracture incidence. The fracture events were identified by radiography. If the fracture site was not mentioned, it was regarded as a nonvertebral fracture. Graft loss was regarded as renal failure, which also included a doubling of the baseline serum creatinine level and undergoing transplantation or dialysis again. We used data from the longest complete follow-up when the outcomes of different follow-up intervals were reported. When investigators published more than one report addressing the same population, the most comprehensive report was included.

Data synthesis and statistical analysis

We initially performed a pairwise meta-analysis using a random-effects model.[17] Results were expressed as odds ratio ( OR ) with 95% confidence intervals ( CI s) for dichotomous variables (fracture, all-cause mortality, graft loss, acute renal rejection, and adverse events) and as the mean difference (MD) for continuous outcomes (percentage change and absolute change in BMD). The level of statistical significance was set at P < 0.05 and all statistical tests were two sided. The statistical heterogeneity of the studies was evaluated by the Cochran's Q test and the I 2 statistic. P ≤ 0.05 for the Q test or an I 2 >50% was suggestive of substantial study heterogeneity.

We performed fixed-effects Bayesian NMAs for indirect and mixed comparisons using Markov chain Monte Carlo methods in WinBUGS version 1.4.3 (MRC Biostatistics Unit).[18] A Bayesian fixed-effects framework was deemed appropriate because of the limited number of studies supporting each edge in the network.[18],[19] We report the resultant effect as MD or OR with corresponding 95% credibility intervals (CrIs), which are the Bayesian analog of 95% CI s. We estimated the relative ranking probability of each strategy and obtained the hierarchy of competing interventions using rankograms and the surface under the cumulative ranking curve (SUCRA).[20] The SUCRA index ranges between 0 (or 0%) and 1 (or 100%), where the treatments with the highest and lowest SUCRA are considered to be the best and worst treatments, respectively.

To assess the presence of inconsistency, we employed the node-splitting method, excluding one direct comparison at a time and estimating the indirect treatment effect for the excluded comparison. To check the assumption of consistency in the entire network, the design-by-treatment model was conducted.[19] We then performed sensitivity analysis to explore important network inconsistencies.

Quality of evidence

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was performed to rate the quality of the evidence.[21] In this approach, direct evidence from the RCTs starts at high quality and can be downgraded based on risk of bias, indirectness, imprecision, inconsistency (or heterogeneity), and publication bias to levels of moderate, low, and relatively low quality.[22]

Results

Study characteristics

Of the 864 citations identified through our search strategy, 23 publications reporting 21 randomized controlled trials (RCTs)[4],[13],[14],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42] were included in this NMA. The PRISMA [15] flowchart depicting the electronic searching process is presented in [Figure 1]. The trials comparing six different bisphosphonates were published between October 1998 and March 2015. [Table 1] provides characteristics of the 21 RCTs involving 1332 participants and additional details are summarized in [Supplement Table 1 [SUPPORTING:2]]. Of these, seven studies [14],[25],[28],[29],[31],[41],[42] excluded patients who were diagnosed with diabetes mellitus. Most of the RCTs included both sexes, except two studies [31],[38] which only included male patients. The number of patients allocated to each treatment ranged from 8 to 66. The duration of patient follow-up ranged from 6 months to 4 years after the first administration.{Figure 1}{Table 1}

With the exception of one RCT,[38] all patients in the included trials received co-intervention including calcium,[4],[29],[31],[32],[33],[36],[37],[39],[41] Vitamin D analogs,[24] or both. As expected, most studies compared bisphosphonates with Vitamin D analogs (cholecalciferol, alfacalcidol, and calcitriol) or placebo treatment. Only two RCTs [13],[14] directly compared two different bisphosphonates. Bisphosphonate interventions encompassed alendronate,[13],[28],[29],[30],[31],[33],[40],[41] pamidronate,[13],[26],[27],[34],[35],[37],[38] zoledronic acid,[4],[32] ibandronate,[14],[23],[36] risedronate,[14],[24],[25],[42] and clodronate.[39] Pamidronate and zoledronic acid were administered intravenously, while clodronate, alendronate, and risedronate were given orally. Ibandronate was given intravenously in two studies and orally in the other studies. The network geometries for the primary outcome of this NMA are provided in [Figure 2].{Figure 2}

Risk of bias assessment result

The results from the risk of bias assessment are provided in [Supplement Figure 1 [SUPPORTING:3]] and [Supplement Table 2 [SUPPORTING:4]]. In general, details regarding trial methodology were unsatisfactory or incomplete for the majority of the studies. Overall, there were 6 (26%) studies regarded as having high risk of bias. Only 10 (43%) studies performed randomized sequence generation adequately. Furthermore, the risk of bias for concealment of treatment allocation was high or unclear in 14 (61%) studies. Only 4 (17%) studies explicitly reported the blinding of participants and investigators, whereas the remaining studies were at high or unclear risk in this regard. The investigators attempted to blind outcome assessors in 6 (26%) studies, 3 studies did not make an effort to blind assessors, and the remaining studies were unclear. Comparison-adjusted funnel plots show no evidence of asymmetry.

Pairwise meta-analysis

The results of the NMA and direct pairwise meta-analysis are summarized in [Supplement Table 3 [SUPPORTING:5]]. In terms of absolute femoral change at the longest follow-up, alendronate combined with calcium was significantly better than calcium alone (MD, 1.15; 95% CI , 0.251-2.049). Alendronate with calcium and Vitamin D analogs was associated with a pronounced improvement in absolute femoral change compared to the combination of calcium and Vitamin D analogs (MD, 0.881; 95% CI , 0.430-1.332). Calcium with Vitamin D analogs was significantly better than solely calcium (MD 0.742; 95% CI , 0.141-1.344). When considering absolute change at the lumbar spine for the longest follow-up, only the combination of alendronate, calcium, and Vitamin D analogs was associated with a marginal improvement compared to calcium and Vitamin D analogs (MD, 0.345; 95% CI , 0.002-0.687). Treatments with calcium alone displayed significantly lower percentage change in BMD at the lumbar spine than with combining calcium and Vitamin D analogs (MD, −2.728; 95% CI , −3.511-−1.945).

Network meta-analysis primary outcome

Change of bone mineral density at the lumbar spine

Eight RCTs involving 490 adults evaluated the percentage change in BMD at the lumbar spine. The staircase diagrams show the MDs and ranks for the treatment comparisons based on SUCRA. We observed that pamidronate combined with calcium and Vitamin D analogs was associated with marked improvement compared to the combination of clodronate and calcium [Figure 3]a; MD, 9.84; 95% CrI, 1.06-19.70]. All bisphosphonates were significantly better than calcium alone except clodronate (MD, 2.85; 95% CrI, −3.78-10.36). Use of solely calcium showed less improvement than combinatorial treatments of calcium with Vitamin D analogs (MD, −6.35; 95% CrI, −10.67-−2.68). However, the addition of either pamidronate or alendronate displayed a notable improvement compared to calcium and Vitamin D (MD, 6.34; 95% CrI, 2.59-11.01 and MD, 6.16; 95% CrI, 0.54-13.24, respectively). The SUCRA values for the regimens were 79%, 72%, 70%, 68%, 66%, 61%, 52%, 31%, and 22% for pamidronate with calcium and Vitamin D analogs, alendronate with calcium and Vitamin D analogs, pamidronate with calcium, ibandronate with calcium and Vitamin D analogs, ibandronate with calcium, clodronate with calcium, alendronate with calcium, calcium alone, and calcium with Vitamin D analogs, respectively.{Figure 3}

When measuring in absolute terms, the results from 15 trials (825 patients) at the longest complete follow-up (ranging from 6 months to 24 months) were less impressive [Figure 3]b. Zoledronic acid and calcium outperformed calcium alone (MD, 0.06; 95% CrI, 0.00-0.12). Pamidronate or alendronate combined with calcium and Vitamin D analogs displayed significant improvement over calcium with or without Vitamin D analogs (MD, 0.05; 95% CrI, 0.02-0.08; MD, 0.12; 95% CrI, 0.01-0.22; MD, 0.04; 95% CrI, 0.01-0.08; and MD, 0.11; 95% CrI, 0.00-0.22, respectively). No differences were observed between other groups. Pamidronate combined with calcium and Vitamin D analogs had the highest SUCRA value (77%), then alendronate plus calcium and Vitamin D (64%), zoledronic acid and calcium (61%), alendronate and calcium (60%), ibandronate with calcium and Vitamin D analogs (59%), risedronate plus calcium and Vitamin D analogs (53%), ibandronate with calcium (48%), clodronate with calcium (42%), calcium plus Vitamin D analogs (35%), and calcium only (20%).

Change of bone mineral density at the femoral neck

Six trials including a total of 308 participants provided data for comparisons of percentage change in BMD at the femoral neck. The ranking of interventions is presented in [Figure 4]a. Only pamidronate or ibandronate combined with calcium demonstrated a significant gain in BMD compared to calcium (MD, 7.02; 95% CrI, 0.30-13.29 and MD, 7.30; 95% CrI, 0.32-14.22, respectively). The SUCRA values for each of the treatment formulations were as follows: pamidronate with calcium (90%), pamidronate with calcium and Vitamin D analogs (82%), calcium plus Vitamin D analogs (80%), ibandronate with calcium (50%), alendronate plus calcium (46%), alendronate with calcium and Vitamin D analogs (27%), clodronate plus calcium (22%), and solely calcium (3%).{Figure 4}

The absolute change in BMD at the femoral neck was analyzed using data from 11 trials (545 patients). Ibandronate with calcium treatment appeared to be advantageous over any other methods [Figure 4]b. Alendronate and calcium with or without Vitamin D analogs showed greater beneficial effects on the BMD than calcium alone (MD, 0.11; 95% CrI, 0.02-0.19 and MD, 0.18; 95% CrI, 0.13-0.31, respectively). Ibandronate plus calcium had the highest SUCRA value (92%), followed by alendronate combined with calcium and Vitamin D analogs (86%), alendronate with calcium (75%), pamidronate with calcium and Vitamin D analogs (51%), calcium with Vitamin D analogs (42%), clodronate plus calcium (28%), zoledronic acid with calcium (21%), and calcium only (6%).

Network meta-analysis: Secondary outcomes

All treatments have uncertain effects on all-cause mortality and graft loss metrics. We did not observe significant differences in the incidences of fractures, including both vertebral and nonvertebral fractures, between the different therapies. No significant differences were detected in the risks of adverse events. Similarly, there were no statistical differences in the number of biopsy-proven acute rejections among different bisphosphonates. Network of included studies for secondary outcomes is shown in [Supplement Figure 2 [SUPPORTING:6]]. Further details of the secondary outcome analyses are presented in [Supplement Table 4 [SUPPORTING:7]].

Network consistency

We did not find any evidence of small study effects based on funnel plot asymmetry, but the number of studies included in each comparison was small. There was no evidence of inconsistency in the NMA when we applied the node-splitting approach [Supplement Figure 3 [SUPPORTING:8]]. The total residual deviance for the outcomes of percentage change (32.22, df = 36) and absolute change (43.86, df = 45) of the BMD at the lumbar spine as well as the percentage change (29.68, df = 28) and absolute change (26.03, df = 28) of the BMD at the femoral neck implied a good model fit. Convergence of chains was verified qualitatively through examining single-trace plots and inspecting the Brooks-Gelman-Rubin diagnostic statistic for values around 1.[43]

Sensitivity analysis

To investigate the different assumptions regarding the potential relationship between time and treatment effect, Bayesian NMAs were repeated using the absolute change of the BMD at the 12-month follow-up period. We observed that the combination of pamidronate with calcium and Vitamin D analogs was significantly more favorable than that of risedronate with calcium and Vitamin D analogs at the lumbar spine [Supplement Table 5a [SUPPORTING:9]]; MD, 0.05; 95% CrI 0.00-0.14]. At the femoral neck, only ibandronate with calcium showed a significant advantage over any other treatments [Supplement Table 5b [SUPPORTING:10]]. When restricting to the first treatment at different times after KT, no significant differences were detected for absolute BMD change at either the lumbar spine or the femoral neck [Supplement Table 6a [SUPPORTING:11]] and [Supplement Table 6b [SUPPORTING:12]]. When restricting to different modes of administration, oral alendronate and calcium with or without Vitamin D analogs showed improvement in absolute BMD compared to calcium alone at the femoral neck (MD, 0.18; 95% CrI, 0.02-0.33 and MD, 0.11; 95% CrI, 0.02-0.20, respectively). The sensitivity analysis results when restricting to immunosuppression regimens found comparable results with the NMA of absolute BMD change at the femoral neck. We excluded three RCTs that only gave corticosteroids and cyclosporine. Ibandronate and calcium was also better than calcium alone or calcium combined with alendronate, Vitamin D analogs, or zoledronic acid (MD, 0.63; 95% CrI, 0.17-1.09; MD, 0.71; 95% CrI, 0.29-1.10; MD, 0.68; 95% CrI, 0.08-0.13; and MD, 0.70; 95% CrI, 0.13-1.15, respectively). We adjusted the results of the primary outcome by excluding 4 (25%) trials that met the criteria for having a high risk of bias. Overall, the results were similar to those of the full analysis, but the statistical power was compromised because of the reduced sample size.

Quality of evidence

In general, there was no serious risk of bias, indirectness, inconsistency, or publication bias for any of the direct comparisons. In several comparisons, there was serious imprecision in the summary estimate because the 95% CrI crossed unity. According to the GRADE, we had high confidence in estimates supporting the additional use of bisphosphonates and moderate confidence in estimates supporting the use of alendronate in combination with calcium or Vitamin D analogs for increasing the absolute change in BMD at both the lumbar spine and the femoral neck. There was low confidence in estimates supporting the superiority of using ibandronate with calcium in terms of the absolute change of the BMD at the femoral neck. Conceptually, there was no significant intransitivity. The GRADE quality of evidence supported the use of each treatment for the primary outcome [Supplement Table 3].

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Until recently, therapeutic options for preventing or treating bone loss of KTRs were controversial. The Kidney Disease Improving Global Outcomes (KDIGO) guideline [44] states that 'bisphosphonates be considered for low BMD patients with stable graft function,' but it was derived from very low-quality evidence. Furthermore, it is still unknown that whether certain treatment regimens are more effective than others. Therefore, we performed indirect and direct comparisons between several bisphosphonate treatments for bone mineral disorders in a NMA. To the best of our knowledge, it is the first NMA to evaluate efficacy and safety of different bisphosphonates in KTRs.

In our study, nearly each bisphosphonate assessed was superior to calcium treatment with regard to percentage change of the BMD at the lumbar spine. It is consistent with previous meta-analyses [12],[45] that indicated bisphosphonates are more effective than calcium with respect to improvement of the BMD at the lumbar spine. When measuring percentage change of the BMD at the femoral neck, only addition of pamidronate or ibandronate offered significant improvement over calcium alone. This result was less prominent than previous studies [12],[45] because we divided bisphosphonates into subclasses and took co-interventions into account. The improvement of the BMD in the appendicular skeleton was less impressive than in the axial skeleton, but that results from the fact that trabecular bone (predominantly present in the lumbar spine) is more active and responds faster than cortical bone (mainly present in the femoral neck).[31]

However, the differences between certain bisphosphonate treatments were not evident. It was surprising that ibandronate with calcium was superior to all other regimens investigated in terms of absolute change at the femoral neck. Ibandronate has previously been approved for postmenopausal osteoporosis in the US.[46] In vitro studies [47] have demonstrated that nitrogen-containing bisphosphonates (alendronate, pamidronate, ibandronate, zoledronate, and risedronate) showed an approximately 10,000-fold greater potency than nonnitrogen-containing drugs (clodronate and etidronate). Yet, the evidence for use of ibandronate was low because only 36 patients in a single trial had treatments of ibandronate with calcium. A simulation study [48] suggested that the probability of being the best may be biased in favor of treatments with a smaller number of studies.

Corticosteroids and calcineurin inhibitors which may affect bone disorders are the cornerstones of immunosuppression after KT.[5],[6] When including RCTs where patients used more than three immunosuppressive drugs, the sensitivity analysis results were comparable at the femoral neck. A retrospective study [49] had confirmed the correlation between cumulative corticosteroid dose and bone damage after KT. However, modern immunosuppression therapy with reduced corticosteroids exposure may explain why we could not detect a significant difference at the lumbar spine. If we only included trials with a 12-month follow-up period, pamidronate would be favored over risedronate at the lumbar spine. Since this result was derived from indirect comparisons, we had low confidence supporting this result. One study [36] gave the first administration immediately before KT, while some other studies [28],[29],[30],[33],[39],[41] gave it after 6 months, when the renal function was stable. We divided the RCTs into two groups according to whether the initial treatment was within 6 months of KT. The included RCTs varied in initial treatment time and lacked direct comparisons and hence finding the differences was difficult.

We found no significant differences between the treatments for secondary outcomes. We did not examine whether co-intervention modified the effects of secondary outcomes, because previous studies [11],[12],[50] did not elucidate significant differences in adverse events risk, fracture rates, or other secondary outcomes between treatment of Vitamin D analogs with calcium or calcium alone. In addition, the included RCTs did not provide sufficient data to make a polygonal network configuration, while there were no significant differences in secondary outcomes in the RCTs themselves. Addition of bisphosphonates did not increase the adverse events risk or cause renal deterioration. These findings suggest that bisphosphonates are well tolerated in KTRs.

We found that bisphosphonates showed a beneficial effect on BMD, but without a decrease in fracture rate. A previous meta-analysis [45] arrived at the same result. Due to low fracture event incidences, small sample sizes, and short follow-up duration in the analyzed studies, the ability of this review to perceive a statistically significant difference in fracture rates was limited. In addition, occult fractures were appraised by radiography in only a few studies. Since adynamic bone disease may occur after bisphosphonate exposure,[51] improvement of BMD is impossible to translate into improved bone histology. Therefore, bone-turnover biomarkers and clinical findings should be interpreted together with BMD. The KDIGO guideline [44] recommends that bone biopsy is reasonable to guide treatment in the first 12 months after transplant, but it was not graded due to a lack of evidence. Furthermore, bone biopsies were not frequently performed, as most centers lacked the expertise to properly process and analyze bone biopsy specimens. Moreover, bone biopsy is an invasive procedure that is poorly tolerated in patients. Until recently, Naylor et al .[52] suggested the Fracture Risk Assessment Tool, while Luckman et al .[53] validated the use of the spine trabecular bone score for KTRs to predict fracture risk. Consequently, all of the included RCTs used BMD as a surrogate marker, despite it being a suboptimal measurement to reflect pathological bone changes and predict fracture risk. Future trials need to find more specific measurements for detecting mineral and bone disorders in KTRs.

Our analysis is strengthened by broad inclusion criteria and a comprehensive search to maximize available data in this field. This NMA updates the previous meta-analysis and performs sensitivity analyses to demonstrate the robustness of estimates. Furthermore, though the authors expressed BMD results using different units, such as g/cm 2, Z-score, T-score, we only included RCTs that used g/cm 2 to express BMD results to standardize the each comparison. We also only included RCTs that investigated adult patients to minimize potential bias and offer more reliable evidence. Moreover, to expand on previous meta-analyses,[12],[45] we took co-intervention (calcium and Vitamin D analogs) into account when we examined the effects of bisphosphonates on BMD.

However, several limitations of our analysis need consideration. First, the omission of important methodological details in the RCTs makes the internal validity difficult to assess. Second, the association between BMD metrics and fracture risk in KTRs is controversial. The short intervention durations and follow-up times in the majority of the included RCTs as well as the different times for initiation of treatment all limit the ability of this NMA to form a conclusion on bisphosphonates and fracture incidence. Moreover, the patients' characteristics, the baseline data of BMD, and the bisphosphonates regimen (dosage, route, timing, and administration duration) differ among the included studies. These factors may potentially influence the calculation of BMD in the RCTs. In addition, most direct comparisons were based on evidence from a single trial, and almost all treatment comparisons were derived from indirect evidence alone. Finally, the sample size of each treatment was very small, which must be considered when making inferences from our study findings.

Looking forward, more correlative measurements than BMD are needed to reflect pathological bone changes in KTRs. Furthermore, since the efficacy of bisphosphonates can be compromised by poor adherence,[54] we need to find an optimal protocol with compliance improvement and better economic benefits. Therefore, high-quality RCTs that compare different bisphosphonates directly with adequate sample sizes and sufficient follow-up time are required to determine the effect of bisphosphonates on fracture incidence.

In conclusion, our NMA suggests that new-generation bisphosphonates such as ibandronate are more favorable in KTRs to improve BMD at the lumbar spine and femoral neck. However, risk of fracture was not reduced by bisphosphonate treatment regimens. Bisphosphonate therapy was well-tolerated in KTRs without an increase in adverse events or graft loss. Because most results were derived from indirect comparisons with small populations, clinicians should take all known safety information and compliance of patients into account when using bisphosphonates. Additional head-to-head trials are needed to support our findings and find an optimal treatment option for KTRs.

Supplementary information is linked to the online version of the paper on the Chinese Medical Journal website.

Acknowledgments

The authors acknowledge Ian Charles Tobias for reviewing the manuscript. Prof. Yi Li and Martina Fu from the Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA, made a great contribution to proofread and revise the manuscript. The authors really appreciate their kindness and contribution.

Financial support and sponsorship

This study was supported by a grant from the National Natural Science Foundation of China (No. 81570668).

Conflicts of interest

There are no conflicts of interest.

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Title Annotation:Meta Analysis
Author:Yang, Yan; Qiu, Shi; Tang, Xi; Li, Xin-Rui; Deng, Ling-Hui; Wei, Qiang; Fu, Ping
Publication:Chinese Medical Journal
Article Type:Report
Date:Apr 15, 2018
Words:6896
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