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

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[89] 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[1112] 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.[1314] 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. Two independent investigators (YY and SQ) initially screened the citation titles and abstracts.

Search algorithms

Click here for additional data file.

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/cm2]) 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 (CIs) 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 I2 statistic. P ≤ 0.05 for the Q test or an I2 >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.[1819] We report the resultant effect as MD or OR with corresponding 95% credibility intervals (CrIs), which are the Bayesian analog of 95% CIs. 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)[413142324252627282930313233343536373839404142] 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. Of these, seven studies[14252829314142] excluded patients who were diagnosed with diabetes mellitus. Most of the RCTs included both sexes, except two studies[3138] 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

Flowchart of study identification and selection procedure.

Table 1

Characteristics of enrolled studies

Studies	Follow-up	Country	Number of patients	Male/female	Intervention	n	Co-intervention	Immunosuppression
Smerud et al., 2012[23]	12 months	Norway	129	99/30	Ibandronate	66	Calcium + calcitriol	Corticosteroids, MMF, CsA or FK506
					Placebo	63
Coco et al., 2012[24]	12 months	USA	42	27/15	Risedronate	20	Calcitriol(with or without calcium)	Corticosteroids, MMF, FK506
					Placebo	22
Omidvar et al., 2011[13]	6 months	Iran	40	27/13	Pamidronate	20	Calcium + calcitriol	Corticosteroids, MMF, CsA
					Alendronate	20
Torregrosa et al.,2010[25]	12 months	Spain	101	67/34	Risedronate	52	Calcium + Vitamin D	Corticosteroids, FK506 with or without MMF
					No treatment	49
Torregrosa et al., 2011[26]	12 months	Spain	39	26/13	Pamidronate	24	Calcium + cholecalciferol	Corticosteroids, MMF, CsA
					Placebo	15
Walsh et al., 2009[27]	24 months	UK	125	69/24	Pamidronate	65	Calcium + Vitamin D	Corticosteroids, CsA
					No treatment	60
Lan et al., 2008[28]	6 months	China	46	19/27	Alendronate	23	Calcium + calcitriol	Corticosteroids, MMF, CsA
					No treatment	23
Trabulus et al., 2008[29]	12 months	Turkey	64	40/19	Alendronate	13	Calcium	Corticosteroids, AZA or MMF, CsA or FK506
					Alfacalcidol	25
					Alendronate + alfacalcidol	17
					No treatment	9
Nayak et al., 2007[30]	6 months	India	50	NA	Alendronate	27	Calcium + Vitamin D	Not mentioned
					No treatment	23
El-Agroudy et al., 2005[31]	12 months	Egypt	60	60/0	Alendronate	15	Calcium	Corticosteroids, CsA
					Alfacalcidol	15
					Calcitonin	15
					No treatment	15
Schwarz et al., 2004[32]	36 months	Austria	20	NA	Zoledronic acid	9	Calcium	Corticosteroids, MMF, CsA
					Placebo	10
Jeffery et al., 2003[33]	12 months	Canada	117	71/26	Alendronate	57	Calcium	Corticosteroids, CsA, AZA or MMF
					Calcitriol	60
Coco et al., 2003[34]	12 months	USA	72	31/28	Pamidronate	36	Calcium + calcitriol	Corticosteroids, CsA or FK506
					No treatment	36
Fan et al., 2003[35]	48 months	UK	17	17/0	Pamidronate	9	No treatment	Corticosteroids, AZA, CsA
					Placebo	8
Haas et al., 2003[4]	6 months	Austria	20	12/8	Zoledronic acid	10	Calcium	Corticosteroids, MMF, CsA
					Placebo	10
Grotz et al., 2001[36]	12 months	Germany	80	48/24	Ibandronate	36	Calcium	Corticosteroids, MMF, CsA
					No treatment	36
Nam et al., 2000[37]	6 months	Korea	50	29/21	Pamidronate	15	Calcium	Not mentioned
					Calcitriol	15
					No treatment	20
Fan et al., 2000[38]	12 months	UK	26	26/0	Pamidronate	14	No treatment	Corticosteroids, AZA, CsA
					Placebo	12
Grotz et al., 1998[39]	12 months	Germany	46	29/17	Clodronate	15	Calcium	Corticosteroids, CsA
					Calcitonin	16
					No treatment	15
Giannini et al., 2001[40]	12 months	Italy	40	27/13	Alendronate	20	Calcium + calcitriol	Corticosteroids, CsA with or without AZA
					No treatment	20
Koc et al., 2002[41]	12 months	Turkey	24	17/7	Alendronate	8	Calcium	Corticosteroids, AZA, CsA
					Calcitriol	8
					No treatment	8
Torregrosa et al., 2007[42]	12 months	Spain	84	42/42	Risedronate	39	Calcium + Vitamin D	Corticosteroids, CsA or FK506, with or without MMF
					No treatment	45
Sánchez-Escuredo et al., 2015[14]	12 months	Spain	77	11/58	Ibandronate	38	Calcium + Vitamin D	Corticosteroids, MMF, CsA or FK506 or mTOR inhibitor
					Risedronate	39

MMF: Mycophenolate mofetil; CsA: Cyclosporine; FK506: Tacrolimus; AZA: Azathioprine; mTOR: Mammalian target of rapamycin.

Supplement Table 1

Treatment characteristics of included studies

Study	Intervention	Administration	Co-intervention
Smerud et al., 2012[23]	Ibandronate	3 mg i.v (every 3 months)	PO calcium 500 mg twice daily + calcitriol 0.25 mcg daily
	Placebo
Coco et al., 2012[24]	Risedronate	35 mg p.o (weekly)	PO calcitriol 0.25 µg daily (with or without calcium)
	Placebo
Omidvar et al., 2011[13]	Pamidronate	90 mg i.v (starting from the 3rd week of transplantation for 3 months)	PO calcium + calcitriol
	Alendronate	70 mg p.o (weekly for 3 months)
Torregrosa et al., 2010[25]	Risedronate	35 mg p.o (weekly)	PO calcium 1.5 g daily + Vitamin D 400 IU daily
	No treatment
Torregrosa et al., 2011[26]	Pamidronate	30 mg i.v (between day 7 and 10 after KT and 3 months post-KT)	PO calcium 1 g daily + cholecalciferol 800 IU daily
	Placebo
Walsh et al., 2009[27]	Pamidronate	1 mg/kg i.v (perioperatively and at month 1, 4, 8, 12)	PO calcium 500 mg daily + Vitamin D 400 IU daily
	No treatment
Lan et al., 2008[28]	Alendronate	70 mg p.o (weekly)	PO calcium 800 mg daily + calcitriol 0.25 µg daily
	No treatment
Trabulus et al., 2008[29]	Alendronate	10 mg p.o (daily)	PO calcium 1 g daily
	Alfacalcidol	0.5 μg p.o (daily)
	Alendronate + alfacalcidol
	No treatment
Nayak et al., 2007[30]	Alendronate	35 mg p.o (weekly)	PO calcium 1 g daily + Vitamin D
	No treatment
El-Agroudy et al., 2005[31]	Alendronate	5 mg p.o (daily)	PO calcium 500 mg daily
	Alfacalcidol	0.5 µg p.o (daily)
	Calcitonin	100 µl intranasally (p.o.d and stopped for 1 month every 3 months)
	No treatment
Schwarz et al., 2004[32]	Zoledronic acid	4 mg i.v (week 2, month 3)	PO calcium 1 g daily
	Placebo
Jeffery et al., 2003[33]	Alendronate	10 mg p.o (daily)	PO calcium 500 mg daily
	Calcitriol	0.25 µg p.o (daily)
Coco et al., 2003[34]	Pamidronate	60 mg i.v (<48 h after KT, 30 mg i.v. at months 1, 2, 3, 6)	PO calcium + calcitriol
	No treatment
Fan et al., 2003[35]	Pamidronate	0.5 mg/kg i.v (preoperatively and at month 1)	No treatment
	Placebo
Haas et al., 2003[4]	Zoledronic acid	4 mg i.v (week 2, month 3)	PO calcium 1 g daily
	Placebo
Grotz et al., 2001[36]	Ibandronate	1 mg i.v just before KTX, 2 mg i.v at month 3, 6, 9	PO calcium 500 mg daily
	No treatment
Nam et al., 2000[37]	Pamidronate	30 mg i.v (every 4 weeks)	PO calcium 500 mg daily
	Calcitriol	0.5 μg p.o (daily)
	No treatment
Fan et al., 2000[38]	Pamidronate	0.5 mg/kg i.v (preoperatively and at month 1)	No treatment
	Placebo
Grotz et al., 1998[39]	Clodronate	800 mg p.o (daily) for 14 days, each followed by 75 days without treatment	PO calcium 500 mg daily
	Calcitonin	100 IU intranasally twice a day
	No treatment
Giannini et al., 2001[40]	Alendronate	10 mg p.o (daily)	PO calcium 500 mg daily + calcitriol 0.5 µg daily
	No treatment
Koc et al., 2002[41]	Alendronate	10 mg p.o (daily)	PO calcium 1 g daily
	Calcitriol	0.5 µg p.o (daily)
	No treatment
Torregrosa et al., 2007[42]	Risedronate	35 mg p.o (weekly)	PO calcium 2.5 g daily + Vitamin D
	No treatment
Sánchez-Escuredo et al., 2015[14]	Ibandronate	150 mg p.o (monthly)	PO calcium 2.5 g daily + Vitamin D 800 IU
	Risedronate	35 mg p.o (weekly)

i.v: Intravenous; p.o and PO: Peros; p.o.d: Per other day; KT: Kidney transplantation.

With the exception of one RCT,[38] all patients in the included trials received co-intervention including calcium,[42931323336373941] 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[1314] directly compared two different bisphosphonates. Bisphosphonate interventions encompassed alendronate,[1328293031334041] pamidronate,[13262734353738] zoledronic acid,[432] ibandronate,[142336] risedronate,[14242542] 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

Network of eligible comparisons for primary outcome. The width of the lines is proportional to the number of trials comparing every pair of treatments, and the size of every circle is proportional to the number of randomly assigned participants (sample size). (a) Percentage change of BMD at lumbar spine. (b) Absolute change of BMD at lumbar spine. (c) Percentage change of BMD at femoral neck. (d) Absolute change of BMD at femoral neck. Pam: Pamidronate; Ale: Alendronate; Clo: Clodronate; Iba: Ibandronate; Zol: Zoledronic acid; Ris: Risedronate; Ca: Calcium; Vit D: Vitamin D analogs; BMD: Bone mineral density.

Risk of bias assessment result

The results from the risk of bias assessment are provided in Supplement Figure 1 and Supplement Table 2. 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.

Supplement Table 2

Risk of bias assessments within studies

Study	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other bias	Risk of bias
Smerud et al., 2012[23]	+	+	+	+	+	+	–	Low
Coco et al., 2012[24]	+	+	+	+	+	+	+	Low
Omidvar et al., 2011[13]	?	?	–	?	+	+	+	High
Torregrosa et al., 2010[25]	+	+	–	?	+	+	+	Moderate
Torregrosa et al., 2011[26]	+	?	+	+	+	+	–	Moderate
Walsh et al., 2009[27]	+	+	–	+	+	+	–	Moderate
Lan et al., 2008[28]	?	?	?	?	+	+	+	Moderate
Trabulus et al., 2008[29]	?	?	–	–	+	+	+	High
Nayak et al., 2007[30]	?	?	?	?	+	+	+	Moderate
El-Agroudy et al., 2005[31]	+	+	+	-	+	+	+	Low
Schwarz et al., 2004[32]	?	?	–	+	+	+	–	High
Jeffery et al., 2003[33]	+	+	–	–	+	+	+	Moderate
Coco et al., 2003[34]	+	+	?	?	+	+	+	Low
Fan et al., 2003[35]	?	-	?	?	+	+	+	High
Haas et al., 2003[4]	?	?	–	+	+	+	–	High
Grotz et al., 2001[36]	?	?	–	?	+	+	+	High
Nam et al., 2000[37]	?	?	?	?	+	–	+	High
Fan et al., 2000[38]	?	-	?	?	+	+	+	High
Grotz et al., 1998[39]	+	+	?	?	+	+	+	Low
Giannini et al., 2001[40]	+	?	?	?	+	+	+	Moderate
Koc et al., 2002[41]	?	+	?	?	+	+	+	Moderate
Torregrosa et al., 2007[42]	?	?	?	?	+	+	+	Moderate
Sánchez-Escuredo et al., 2015[14]	?	–	–	?	+	+	+	High

We used an updated “risk of bias” tool from the Cochrane Collaboration recommends. This tool addresses seven specific bias domains including methods for generating the random sequence, allocation concealment, blinding of participants and investigators, blinding of outcome assessment, incompleteness of outcome data, and selective outcome reporting. Each item is adjudicated within each study and the results are represented in a risk of bias table. We considered allocation concealment adequate if the investigators responsible for patient selection were unable to suspect before allocation which treatment was next. We considered blinding of patients adequate if interventions were described as indistinguishable, or if double-dummy technique was used. We considered blinding of therapists adequate if it was explicitly mentioned in the text that therapists were blinded. We considered statistical analyses to be adequate if all randomized patients were included in the analysis according to the intention-to-treat principle. We considered incomplete outcome data if it excluded at least one of the randomly assigned patients from the analysis. ?: Unclear risk of bias; +: Low risk of bias; –: High risk of bias.

Risk of bias assessments within studies. (a) Risk of bias graph: Review authors’ judgments about each risk of bias item presented as percentages across all included studies. (b) Study.level risk of bias.

Click here for additional data file.

Pairwise meta-analysis

The results of the NMA and direct pairwise meta-analysis are summarized in Supplement Table 3. 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).

Supplement Table 3

Results of NMA and direct pairwise meta-analysis for change of BMD

Comparisons	Number of events (participants)	Pairwise meta-analysis MDs (95% CI)	Network meta-analysis MDs (95% CrI)	Heterogeneity I2 (%)	Cochran's Q (P)	Quality of evidence
Percentage change at lumbar spine
Pamidronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	2 (152)	37.821 (−35.383, 111.024)	6.34 (2.59, 11.01)	99.10	0.000	⊕ low
Calcium versus calcium + Vitamin D analogs	2 (51)	−2.728 (−3.511, −1.945)	−6.35 (−10.67, −2.68)	0.00	0.373	⊕⊕⊕ moderate
Absolute change at lumbar spine
Pamidronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	3 (181)	2.286 (−0.572, 5.144)	0.05 (0.02, 0.08)	97.70	0.000	⊕ low
Alendronate + calcium versus calcium + Vitamin D analogs	4 (176)	0.191 (−0.108, 0.489)	0.02 (−0.03, 0.07)	0.00	0.866	⊕⊕⊕ moderate
Alendronate + calcium versus calcium	2 (46)	0.577 (−0.014, 1.168)	0.09 (−0.01, 0.19)	0.00	0.728	⊕⊕⊕ moderate
Alendronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	3 (134)	0.345 (0.002, 0.687)	0.04 (0.01, 0.08)	0.00	0.956	⊕⊕⊕ moderate
Calcium versus calcium + Vitamin D analogs	2 (46)	−0.403 (−0.987, 0.182)	−0.07 (−0.17, 0.03)	0.00	0.960	⊕⊕⊕ moderate
Percentage change at femoral neck
Calcium versus calcium + Vitamin D analogs	2 (51)	−1.427 (−2.873, 0.020)	−3.70 (−10.27, 2.97)	79.30	0.028	⊕⊕ low
Absolute change at femoral neck
Pamidronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	2 (122)	0.028 (−0.331, 0.387)	0.01 (−0.10, 0.15)	0.00	0.756	⊕⊕⊕ moderate
Alendronate + calcium versus calcium + Vitamin D analogs	4 (176)	0.348 (−0.076, 0.772)	0.04 (−0.03, 0.10)	38.10	0.184	⊕⊕⊕ moderate
Alendronate + calcium versus calcium	2 (46)	1.150 (0.251, 2.049)	0.11 (0.02, 0.19)	48.10	0.165	⊕⊕⊕ moderate
Alendronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	2 (84)	0.881 (0.430, 1.332)	0.10 (−0.01, 0.21)	0.00	0.382	⊕⊕ low
Calcium versus calcium + Vitamin D analogs	2 (46)	−0.742 (−1.344, −0.141)	−0.07 (−0.16, 0.03)	0.00	0.403	⊕⊕ low
Absolute change at lumbar spine 12-month follow-up
Pamidronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	2 (88)	3.466 (−2.485, 9.416)	0.05 (0.01, 0.10)	98.40	0.000	⊕ low
Alendronate + calcium versus calcium + Vitamin D analogs	4 (176)	0.191 (−0.108, 0.489)	0.04 (0.00, 0.09)	0.00	0.866	⊕⊕ low
Alendronate + calcium versus calcium	2 (46)	0.577 (−0.014, 1.168)	0.07 (−0.04, 0.18)	0.00	0.728	⊕⊕⊕ moderate
Calcium versus calcium + Vitamin D analogs	2 (46)	−0.403 (−0.987, 0.182)	−0.03 (−0.14, 0.08)	0.00	0.960	⊕⊕⊕ moderate
Absolute change at femoral neck 12-month follow-up
Alendronate+calcium versus calcium + Vitamin D analogs	4 (176)	0.348 (−0.076, 0.772)	0.04 (−0.07, 0.16)	38.10	0.148	⊕⊕⊕ moderate
Alendronate + calcium versus calcium	2 (46)	1.150 (0.251, 2.049)	0.11 (−0.04, 0.27)	48.10	0.165	⊕⊕ low
Calcium versus calcium + Vitamin D analogs	2 (46)	−0.742 (−1.344, −0.141)	−0.07 (−0.24, 0.08)	0.00	0.403	⊕⊕ low

Comparing evidence from the Network meta-analysis with evidence obtained from the only possible pairwise meta-analysis conducted. All MD in bold are statistically significant. CIs: Confidence intervals; CrI: Credible interval. Using GRADE to rate quality of evidence from a network meta-analysis involved several steps: First, we rated quality of evidence for direct comparisons; second, we rated quality of evidence for indirect estimates (starting at the lowest rating of the two pairwise direct estimates that contribute as first-order loops to the indirect estimate, which can be rated down further for imprecision or intransitivity), and then third, rating the quality of evidence for the network combining direct and indirect estimates. In this step, if direct and indirect estimates from second-order comparisons are similar, the higher of the ratings was assigned to the network meta-analysis estimates. NMA: Network meta-analysis; BMD: Bone mineral density; MDs: Mean differences. ⊕ means meet the GRADE criteria, the more ⊕ means the quality of evidence was higher.

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 3a; 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

Summary mean difference and 95% credible intervals from network meta-analysis of change of BMD at the lumbar spine. The results of the plots are read from top to bottom and left to right. Significant results are in bold. (a) Percentage change; (b) absolute change. BMD: Bone mineral density.

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 3b]. 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 4a. 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

Summary mean difference and 95% credible intervals from network meta-analysis of change of BMD at the femoral neck. The results of the plots are read from top to bottom and left to right. Significant results are in bold. (a) Percentage change; (b) absolute change. BMD: Bone mineral density.

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 4b]. 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. Further details of the secondary outcome analyses are presented in Supplement Table 4.

Supplement Table 4

Network meta-analysis of secondary outcomes

A. Adverse events
Clodronate
0.65 (0.01, 30.30)	Alendronate
0.55 (0.01, 25.68)	0.86 (0.12, 5.14)	Pamidronate
0.38 (0.01, 12.76)	0.58 (0.14, 2.38)	0.68 (0.14, 3.80)	Control
0.29 (0.00, 18.12)	0.44 (0.04, 5.40)	0.51 (0.05, 8.18)	0.75 (0.11, 6.16)	Risedronate
0.19 (0.00, 10.60)	0.29 (0.04, 3.23)	0.34 (0.04, 4.48)	0.51 (0.10, 3.19)	0.67 (0.09, 5.37)	Ibandronate
B. Fracture incidences
Zoledronic acid
0.77 (0.07, 8.89)	Control
0.74 (0.04, 13.84)	1.01 (0.19, 5.07)	Ibandronate
0.70 (0.05, 11.46)	0.94 (0.31, 3.31)	0.98 (0.13, 7.27)	Risedronate
0.47 (0.03, 8.05)	0.62 (0.18, 2.33)	0.62 (0.09, 5.27)	0.66 (0.11, 4.11)	Pamidronate
0.27 (0.00, 13.51)	0.40 (0.01, 8.92)	0.39 (0.01, 12.94)	0.42 (0.01, 11.05)	0.64 (0.01, 20.45)	Clodronate
C. Vertebral fracture incidences
Zoledronic acid
0.92 (0.06, 12.86)	Control
0.91 (0.03, 25.66)	0.98 (0.14, 7.11)	Ibandronate
0.88 (0.04, 18.15)	0.93 (0.25, 4.28)	0.92 (0.09, 11.64)	Risedronate
0.56 (0.01, 21.66)	0.57 (0.03, 8.46)	0.61 (0.02, 16.49)	0.63 (0.02, 11.72)		Pamidronate
D. Nonvertebral fracture incidences
Control
0.99 (0.04, 23.04)	Ibandronate
0.57 (0.08, 5.17)	0.61 (0.01, 26.83)		Pamidronate
0.37 (0.01, 12.52)	0.35 (0.00, 37.25)		0.61 (0.01, 34.30)		Clodronate
E. All-cause mortality
Pamidronate
0.35 (0.00, 57.04)	Alendronate
0.14 (0.00, 3.33)	0.41 (0.01, 11.30)	Control
0.05 (0.00, 6.23)	0.14 (0.00, 18.90)	0.38 (0.01, 11.12)	Clodronate
0.05 (0.00, 5.27)	0.13 (0.00, 16.76)	0.36 (0.01, 10.45)	0.93 (0.01, 207.30)	Risedronate
0.06 (0.00, 2.13)	0.17 (0.00, 7.26)	0.43 (0.05, 2.80)	1.10 (0.02, 104.81)	1.16 (0.02, 81.58)	Ibandronate
F. Graft loss
Alendronate
0.38 (0.01, 19.44)	Risedronate
0.34 (0.01, 9.83)	0.89 (0.12, 5.14)	Control
0.29 (0.01, 13.14)	0.75 (0.05, 9.52)	0.83 (0.14, 5.16)	Pamidronate
0.28 (0.01, 14.25)	0.72 (0.06, 10.51)	0.80 (0.16, 5.88)	0.95 (0.08, 14.31)	Ibandronate
0.05 (0.00, 6.96)	0.15 (0.00, 6.00)	0.18 (0.00, 4.33)	0.21 (0.00, 7.97)	0.21 (0.00, 7.37)	Clodronate
G. Biopsy-proven acute rejections
Alendronate
0.59 (0.13, 2.86)	Control
0.30 (0.01, 6.56)	0.53 (0.03, 7.21)	Zoledronic acid
0.32 (0.05, 2.24)	0.56 (0.18, 1.73)	1.04 (0.06, 27.70)	Pamidronate
0.27 (0.04, 1.94)	0.47 (0.13, 1.44)	0.87 (0.05, 21.42)	0.82 (0.15, 4.29)	Ibandronate

Summary OR and 95% CrIs from network meta-analysis of secondary outcomes. Comparisons should be read from left to right. The response rate and remission rate estimate is located at the intersection of the column-defining treatment and the row-defining treatment. An OR value below 1 favors the column-defining treatment. To obtain ORs for comparisons in the opposing direction, reciprocals should be taken. Significant results are in bold. ORs: Odds ratios; CrIs: Credible intervals.

Network of eligible comparisons for secondary outcome. The width of the lines is proportional to the number of trials comparing every pair of treatments, and the size of every circle is proportional to the number of randomly assigned participants (sample size). (a) Adverse events; (b) fracture incidence; (c) vertebral fracture; (d) nonvertabral fracture; (e) all-cause mortality; (f) graft loss; (g) biopsy-proven acute rejections.

Click here for additional data file.

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]. 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]

Network consistency of primary outcomes. (a) Network consistency of percentage change of BMD at lumbar spine. A: Pamidronate + calcium; B: Pamidronate + calcium + Vitamin D analogs; C: Alendronate + calcium; D: Alendronate + calcium + Vitamin D analogs; E: Clodronate + calcium; F: Ibandronate + calcium; G: Ibandronate + calcium + Vitamin D analogs; H: Calcium; I: Calcium + Vitamin D analogs. (b) Network consistency of absolute change of BMD at lumbar spine. A: Pamidronate + calcium + Vitamin D analogs; B: Alendronate + calcium; C: Alendronate + calcium + Vitamin D analogs; D: Risedronate + calcium + Vitamin D analogs; E: Clodronate + calcium; F: Ibandronate + calcium; G: Ibandronate + calcium + Vitamin D analogs; H: Zoledronic acid + calcium; I: Calcium; J: Calcium + Vitamin D analogs. (c) Network consistency of percentage change of BMD at femoral neck. A: Pamidronate + calcium; B: Pamidronate + calcium + Vitamin D analogs; C: Alendronate + calcium; D: Alendronate + calcium + Vitamin D analogs; E: Clodronate + calcium; F: Ibandronate + calcium; G: Calcium; H: Calcium + Vitamin D analogs. (d) Network consistency of absolute change of BMD at femoral neck. A: Pamidronate + calcium + Vitamin D analogs; B: Alendronate + calcium; C: Alendronate + calcium + Vitamin D analogs; D: Clodronate + calcium; E: Ibandronate + calcium; F: Zoledronic acid + calcium; G: Calcium; H: Calcium + Vitamin D analogs. BMD: Bone mineral density. * means it was direct evidence.

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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; 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]. 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 Tables 6a and 6b]. 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.

Supplement Table 5a

Subgroup analysis of league tables of absolute change of BMD at lumbar spine for 12-month follow-up from analysis

Pamidronate + calcium + Vitamin D analogs
0.00 (−0.11, 0.11)	Alendronate + calcium + Vitamin D analogs
0.01 (−0.06, 0.09)	0.02 (−0.09, 0.11)	Alendronate + calcium
0.03 (−0.06, 0.11)	0.03 (−0.07, 0.15)	0.02 (−0.06, 0.10)	Ibandronate + calcium + Vitamin D analogs
0.01 (−0.14, 0.16)	0.02 (−0.14, 0.19)	0.00 (−0.13, 0.15)	−0.01 (−0.18, 0.13)	Ibandronate + calcium
0.05 (0.00, 0.14)	0.06 (−0.06, 0.17)	0.04 (−0.05, 0.13)	0.02 (−0.07, 0.12)	0.04 (−0.13, 0.20)	Risedronate + calcium + Vitamin D analogs
0.05 (0.01, 0.10)	0.05 (−0.04, 0.15)	0.04 (0.00, 0.09)	0.02 (−0.04, 0.08)	0.04 (−0.10, 0.19)	0.00 (−0.07, 0.07)	Calcium + Vitamin D analogs
0.04 (−0.39, 0.52)	0.06 (−0.41, 0.54)	0.04 (−0.41, 0.50)	0.02 (−0.42, 0.49)	0.03 (−0.43, 0.49)	0.00 (−0.45, 0.48)	0.00 (−0.44, 0.46)	Clodronate + calcium
0.08 (−0.04, 0.19)	0.09 (−0.05, 0.23)	0.07 (−0.04, 0.18)	0.05 (−0.07, 0.17)	0.07 (0.00, 0.16)	0.03 (−0.10, 0.16)	0.03 (−0.08, 0.14)	0.03 (−0.43, 0.49)	Calcium

For each comparison, the random effects model MD and 95% CrIs are provided. The results of the plots are read from top to bottom and left to right. Significant results are in bold. MD: Mean difference; BMD: Bone mineral density; CrIs: Credible intervals.

Supplement Table 5b

Subgroup analysis of league tables of absolute change of BMD at femoral neck for 12-month follow-up from analysis

Ibandronate + calcium
0.53 (0.20, 0.85)	Alendronate + calcium + Vitamin D analogs
0.61 (0.35, 0.90)	0.08 (−0.11, 0.29)	Alendronate + calcium
0.65 (0.37, 0.94)	0.12 (−0.07, 0.35)	0.04 (−0.07, 0.16)	Calcium + Vitamin D analogs
0.66 (0.33, 0.99)	0.14 (−0.18, 0.46)	0.06 (−0.19, 0.31)	0.02 (−0.20, 0.23)	Pamidronate + calcium + Vitamin D analogs
0.70 (0.42, 1.02)	0.18 (−0.14, 0.50)	0.10 (−0.16, 0.37)	0.06 (−0.24, 0.32)	0.04 (−0.30, 0.40)	Clodronate + calcium
0.72 (0.51, 0.93)	0.19 (−0.05, 0.44)	0.11 (−0.04, 0.27)	0.07 (−0.08, 0.24)	0.05 (−0.22, 0.34)	0.01 (−0.21, 0.23)	Calcium

For each comparison, the random effects model MD and 95% CrIs are provided. The results of the plots are read from top to bottom and left to right. Significant results are in bold. MD: Mean difference, CrIs: Credible intervals; BMD: Bone mineral density.

Supplement Table 6a

Subgroup analysis and sensitivity analysis of absolute change of BMD at lumbar spine

Treatment comparison	MD (95% CrI)
Absolute change of BMD at lumbar spine	Overall	Treatment time after kidney transplantation		Modes of administration		Immunosuppression regime
		Before 6 months	After 6 months	i.v	PO
Pamidronate + calcium + Vitamin D analogs versus alendronate + calcium + Vitamin D analogs	0.01 (−0.03, 0.04)	−0.03 (−1.21, 0.80)	–	−0.03 (−1.23, 1.00)	–	0.01 (−0.06, 0.09)
Pamidronate + calcium + Vitamin D analogs versus zoledronic acid + calcium	0.06 (−0.07, 0.18)	0.12 (−1.23, 1.69)	–	0.24 (−0.56, 1.05)	–	0.04 (−0.15, 0.22)
Pamidronate + calcium + Vitamin D analogs versus alendronate + calcium	0.03 (−0.03, 0.08)	−0.06 (−1.26, 0.98)	–	–	–	0.03 (−0.07, 0.13)
Pamidronate + calcium + Vitamin D analogs versus ibandronate + calcium + Vitamin D	0.03 (−0.02, 0.08)	0.05 (−1.08, 1.34)	–	0.00 (−0.01, 0.01)	–	0.03 (−0.08, 0.16)
Pamidronate + calcium + Vitamin D analogs versus risedronate + calcium + Vitamin D analogs	0.05 (−0.01, 0.12)	0.04 (−1.13, 1.16)	–	–	–	0.05 (−0.07, 0.18)
Pamidronate + calcium + Vitamin D analogs versus ibandronate + calcium	0.05 (−0.08, 0.20)	–	–	0.24 (−0.56, 1.06)	–	0.04 (−0.14, 0.23)
Pamidronate + calcium + Vitamin D analogs versus clodronate + calcium	0.09 (−0.04, 0.21)	–	–	–	–	–
Pamidronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	0.05 (0.02, 0.08)	0.07 (−0.59, 0.64)	–	0.07 (−0.59, 0.84)	–	0.05 (−0.03, 0.14)
Pamidronate + calcium + Vitamin D analogs versus calcium	0.12 (0.01, 0.22)	0.15 (−1.16, 1.14)	–	0.24 (−0.56, 1.05)	–	0.10 (−0.07, 0.28)
Alendronate + calcium + Vitamin D analogs versus zoledronic acid + calcium	0.05 (−0.07, 0.18)	0.16 (−1.38, 2.21)		0.24 (−0.56, 1.05)	–	0.03 (−0.14, 0.19)
Alendronate + calcium + Vitamin D analogs versus alendronate + calcium	0.02 (−0.04, 0.08)	−0.03 (−1.38, 1.60)	0.02 (−0.05, 0.10)	–	−0.01 (−0.04, 0.04)	0.02 (−0.06, 0.11)
Alendronate + calcium + Vitamin D analogs versus ibandronate + calcium + Vitamin D	0.02 (−0.04, 0.07)	0.09 (−1.37, 2.00)	–	0.03 (−1.75, 1.84)	–	0.02 (−0.09, 0.12)
Alendronate + calcium + Vitamin D analogs versus risedronate + calcium + Vitamin D analogs	0.04 (−0.03, 0.11)	0.07 (−1.30, 1.72)	–	–	0.14 (−0.77, 1.77)	0.04 (−0.06, 0.15)
Alendronate + calcium + Vitamin D analogs versus ibandronate + calcium	0.05 (−0.09, 0.19)	–	–	0.24 (−0.56, 1.05)	–	0.03 (−0.15, 0.21)
Alendronate + calcium + Vitamin D analogs versus clodronate + calcium	0.08 (−0.04, 0.21)	–	0.06 (−0.12, 0.25)	–	0.15 (−0.77, 1.79)	–
Alendronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	0.04 (0.01, 0.08)	0.10 (−0.10, 1.47)	0.04 (−0.02, 0.09)	0.10 (−1.16, 1.60)	0.05 (−4.91, 5.00)	0.04 (−0.02, 0.11)
Alendronate + calcium + Vitamin D analogs versus calcium	0.11 (0.00, 0.22)	0.18 (−1.27, 1.45)	0.09 (−0.07, 0.24)	0.24 (−0.56, 1.05)	0.15 (−0.76, 1.79)	0.09 (−0.07, 0.25)
Zoledronic acid + calcium versus alendronate + calcium	−0.03 (−0.15, 0.09)	−0.18 (−1.62, 1.09)	–	–	–	−0.01 (−0.16, 0.16)
Zoledronic acid + calcium versus ibandronate + calcium + Vitamin D analogs	−0.03 (−0.16, 0.09)	−0.07 (−1.94, 1.49)	–	−0.24 (−1.06, 0.56)	–	−0.01 (−0.18, 0.17)
Zoledronic acid + calcium versus risedronate + calcium+ Vitamin D analogs	−0.01 (−0.14, 0.13)	−0.09 (−1.93, 1.59)	–	–	–	0.01 (−0.16, 0.20)
Zoledronic acid + calcium versus ibandronate + calcium	0.00 (−0.11, 0.10)	–	–	0.03 (−1.23, 1.69)	–	0.00 (−0.12, 0.13)
Zoledronic acid + calcium versus clodronate + calcium	0.03 (−0.06, 0.13)	–	–	–	–	–
Zoledronic acid + calcium versus calcium + Vitamin D analogs	−0.01 (−0.13, 0.11)	−0.06 (−1.54, 1.16)	–	−0.24 (−1.05, 0.56)	–	0.01 (−0.16, 0.17)
Zoledronic acid + calcium versus calcium	0.06 (0.00, 0.12)	0.03 (−1.37, 1.00)	–	0.08 (−0.87, 1.42)	–	0.06 (−0.02, 0.14)
Alendronate + calcium versus ibandronate + calcium + Vitamin D analogs	0.00 (−0.06, 0.06)	0.11 (−1.22, 1.78)	–	–	–	−0.01 (−0.11, 0.09)
Alendronate + calcium versus risedronate + calcium + Vitamin D analogs	0.02 (−0.05, 0.10)	0.10 (−1.27, 1.82)	–	–	0.14 (−0.77, 1.78)	0.02 (−0.08, 0.12)
Alendronate + calcium versus ibandronate + calcium	0.03 (−0.10, 0.17)	–	–	–	–	0.01 (−0.17, 0.18)
Alendronate + calcium versus clodronate + calcium	0.06 (−0.06, 0.18)	–	0.04 (−0.13, 0.22)	–	0.15 (−0.77, 1.79)	–
Alendronate + calcium versus calcium + Vitamin D analogs	0.02 (−0.03, 0.07)	0.13 (−0.83, 1.33)	0.02 (−0.04, 0.07)	–	0.05 (−2.59, 2.97)	0.02 (−0.04, 0.08)
Alendronate + calcium versus calcium	0.09 (−0.01, 0.19)	0.21 (−0.85, 1, 17)	0.07 (−0.07, 0.22)	–	0.15 (−0.77, 1.78)	0.07 (−0.08, 0.20)
Ibandronate + calcium + Vitamin D analogs versus risedronate + calcium + Vitamin D analogs	0.02 (−0.05, 0.09)	−0.01 (−1.45, 1.21)	–	–	–	0.02 (−0.08, 0.15)
Ibandronate + calcium + Vitamin D analogs versus ibandronate + calcium	0.03 (−0.11, 0.18)	–	–	0.24 (−0.56, 1.06)	–	0.01 (−0.17, 0.21)
Ibandronate + calcium + Vitamin D analogs versus clodronate + calcium	0.06 (−0.06, 0.19)	–	–	–	–	–
Ibandronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	0.02 (−0.02, 0.07)	0.01 (−0.97, 0.94)	–	0.07 (−0.85, 1.28)	–	0.02 (−0.05, 0.11)
Ibandronate + Calcium + Vitamin D analogs versus calcium	0.09 (−0.02, 0.20)	0.10 (−1.47, 1.18)	–	0.24 (−0.56, 1.06)	–	0.07 (−0.09, 0.23)
Risedronate + calcium + Vitamin D analogs versus ibandronate + calcium	0.00 (−0.15, 0.16)	–	–	–	–	−0.01 (−0.20, 0.19)
Risedronate + calcium + Vitamin D analogs versus clodronate + calcium	0.04 (−0.10, 0.17)	–	–	–	0.75 (−4.58, 7.05)	–
Risedronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	0.00 (−0.06, 0.05)	0.03 (−0.88, 1.04)	–	–	−0.13 (−0.76, 1.77)	0.00 (−0.09, 0.08)
Risedronate + calcium + Vitamin D analogs versus calcium	0.07 (−0.05, 0.18)	0.11 (−1.47, 1.31)	–	–	0.73 (−3.56, 4.94)	0.05 (−0.11, 0.21)
Ibandronate + calcium versus clodronate + calcium	0.04 (−0.08, 0.14)	–	–	–	–	–
Ibandronate + calcium versus calcium + Vitamin D analogs	−0.01 (−0.14, 0.12)	–	–	−0.24 (−1.05, 0.56)	–	0.01 (−0.17, 0.19)
Ibandronate + calcium versus calcium	0.06 (−0.02, 0.15)	–	–	0.05 (−1.08, 1.25)	–	0.06 (−0.04, 0.16)
Clodronate + calcium versus calcium + Vitamin D analogs	−0.04 (−0.16, 0.08)	–	−0.02 (−0.20, 0.15)	–	−0.14 (−1.79, 0.77)	–
Clodronate + calcium versus calcium	0.03 (−0.04, 0.10)	–	0.03 (−0.07, 0.12)	–	−0.03 (−4.72, 4.11)	–
Calcium + Vitamin D analogs versus calcium	0.07 (−0.03, 0.17)	0.08 (−1.07, 0.96)	0.05 (−0.09, 0.20)	0.24 (−0.57, 1.05)	0.15 (−0.76, 1.79)	0.05 (−0.10, 0.20)

i.v: Intravenous; PO: Peros; Immunosuppression regimen included >3 drugs that contained corticosteroid, calcineurin inhibitors (cyclosporine or tacrolimus). Significant results are in bold. CrI: Credible interval; BMD: Bone mineral density; MD: Mean difference. –: No enough data to provide information about the results.

Supplement Table 6b

Subgroup analysis and sensitivity analysis of absolute change of BMD at femoral neck

Treatment comparison	MD (95% CrI)
Absolute change of BMD at femoral neck	Overall	Treatment time after kidney transplantation		Modes of administration		Immunosuppression regime
		Before 6 months	After 6 months	i.v	PO
Ibandronate + calcium versus alendronate+ calcium+ Vitamin D analogs	0.54 (0.34, 0.73)	–	–	−0.14 (−1.77, 0.77)	–	0.59 (−0.03, 1.07)
Ibandronate + calcium versus alendronate + calcium	0.60 (0.44, 0.76)	–	–	–	–	0.63 (0.17, 1.09)
Ibandronate + calcium versus pamidronate + calcium + Vitamin D analogs	0.63 (0.39, 0.83)	–	–	−0.14 (−1.78, 0.77)	–	0.66 (−0.02, 1.12)
Ibandronate + calcium versus calcium + Vitamin D analogs	0.64 (0.47, 0.80)	–	–	−0.13 (−0.77, 1.77)	–	0.68 (0.08, 1.13)
Ibandronate + calcium versus clodronate + calcium	0.70 (0.51, 0.89)	–	–	–	–	–
Ibandronate + calcium versus zoledronic acid + calcium	0.71 (0.52, 0.91)	–	–	0.75 (−4.58, 7.05)	–	0.70 (0.13, 1.15)
Ibandronate + calcium versus calcium	0.71 (0.58, 0.84)	–	–	0.73 (−3.56, 4.94)	–	0.71 (0.29, 1.10)
Alendronate + calcium + Vitamin D analogs versus alendronate + calcium	0.07 (−0.06, 0.18)	0.06 (−5.42, 5.47)	0.08 (−0.13, 0.28)	–	0.07 (0.06, −0.19)	0.04 (−0.22, 0.32)
Alendronate + calcium + Vitamin D analogs versus pamidronate + calcium + Vitamin D analogs	0.09 (−0.08, 0.23)	−0.02 (−3.57, 3.42)	–	−0.01 (−3.80, 3.77)	–	0.07 (−0.27, 0.31)
Alendronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	0.10 (−0.01, 0.21)	0.07 (−3.98, 4.28)	0.11 (−0.08, 0.32)	0.05 (−4.91, 5.00)	0.12 (−0.01, 0.23)	0.09 (−0.15, 0.30)
Alendronate + calcium + Vitamin D analogs versus clodronate + calcium	0.17 (−0.05, 0.36)	–	0.14 (−0.20, 0.46)	–	0.18 (−0.02, 0.39)	–
Alendronate + calcium + Vitamin D analogs versus zoledronic acid + calcium	0.17 (−0.03, 0.36)	0.22 (−5.93, 7.83)	–	0.15 (−0.77, 1.79)	–	0.12 (−0.39, 0.69)
Alendronate + calcium + Vitamin D analogs versus calcium	0.18 (0.03, 0.31)	0.19 (−4.88, 5.79)	0.15 (−0.14, 0.41)	0.15 (−0.76, 1.79)	0.18 (0.02, 0.33)	0.13 (−0.27, 0.46)
Alendronate + calcium versus pamidronate + calcium + Vitamin D analogs	0.02 (−0.13, 0.16)	−0.08 (−5.00, 4.34)	–	–	–	0.02 (−0.35, 0.35)
Alendronate + calcium versus calcium + Vitamin D analogs	0.04 (−0.03, 0.10)	0.01 (−3.87, 3.89)	0.03 (−0.10,0.17)	–	0.04 (−0.03, 0.11)	0.05 (−0.21, 0.23)
Alendronate + calcium versus clodronate + calcium	0.10 (−0.08, 0.27)	–	0.06 (−0.30, 0.37)	–	0.10 (−0.05, 0.30)	–
Alendronate + calcium versus zoledronic acid + calcium	0.10 (−0.07, 0.28)	0.17 (−5.95, 6.16)	–	–	–	0.07 (−0.42, 0.55)
Alendronate + calcium versus calcium	0.11 (0.02, 0.19)	0.14 (−3.74, 4.02)	0.07 (−0.16, 0.29)	–	0.11 (0.02, 0.20)	0.08 (−0.26, 0.40)
Pamidronate + calcium + Vitamin D analogs versus calcium + Vitamin D analogs	0.01 (−0.10, 0.15)	0.09 (−2.33, 2.53)	–	0.05 (−2.59, 2.97)	–	0.03 (−0.24, 0.32)
Pamidronate + calcium + Vitamin D analogs versus clodronate + calcium	0.08 (−0.14, 0.29)	–	–	–	–	–
Pamidronate + calcium + Vitamin D analogs versus zoledronic acid + calcium	0.08 (−0.12, 0.32)	0.25 (−5.11, 6.92)	–	0.15 (−0.77, 1.79)	–	0.05 (−0.47, 0.64)
Pamidronate + calcium + Vitamin D analogs versus calcium	0.09 (−0.07, 0.27)	0.22 (−4.01, 4.69)	–	0.15 (−0.77, 1.78)	–	0.06 (−0.32, 0.53)
Calcium + Vitamin D analogs versus clodronate + calcium	0.06 (−0.13, 0.23)	–	0.03 (−0.31, 0.33)	–	0.06 (−0.11, 0.25)	–
Calcium + Vitamin D analogs versus zoledronic acid + calcium	0.07 (−0.10, 0.24)	0.15 (−4.95, 5.60)	–	0.15 (−0.77, 1.79)	–	0.02 (−0.41, 0.52)
Calcium + Vitamin D analogs versus calcium	0.07 (−0.03, 0.16)	0.12 (−3.26, 3.75)	0.04 (−0.19, 0.27)	0.15 (−0.76, 1.79)	0.07 (−0.04, 0.18)	0.03 (−0.25, 0.38)
Clodronate + calcium versus zoledronic acid + calcium	0.00 (−0.20, 0.21)	–	–	–	–	–
Clodronate + calcium versus calcium	0.01 (−0.12, 0.16)	–	0.01 (−0.22, 0.25)	–	0.01 (−0.15, 0.15)	–
Zoledronic acid + calcium versus calcium	0.01 (−0.14, 0.16)	−0.03 (−3.62, 3.71)	–	−0.03 (−4.72, 4.11)	–	0.01 (−0.35, 0.37)

i.v: Intravenous; PO: Peros; Immunosuppression regimen included >3 drugs that contained corticosteroid, calcineurin inhibitors (cyclosporine or tacrolimus). Significant results are in bold. CrI: Credible interval; BMD: Bone mineral density; MD: Mean difference. –: No enough data to provide information about the results.

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].

DISCUSSION

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[1245] 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[1245] 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.[56] 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[282930333941] 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[111250] 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/cm2, Z-score, T-score, we only included RCTs that used g/cm2 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,[1245] 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.

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.