Efficacy and safety of medical therapy for low bone mineral density in patients with Crohn disease: A systematic review with network meta-analysis

Abstract

Background: Low bone mineral density (BMD) is a frequent complication of inflammatory bowel disease (IBD), particularly in patients with Crohn disease (CD). The aim of our study is to determine the efficacy and safety of different drugs used to treat low BMD in patients with CD.

Methods: PUBMED/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched for eligible studies. A random-effects model within a Bayesian framework was applied to compare treatment effects as standardized mean difference (SMD) with their corresponding 95% credible interval (CrI), while odds ratio (OR) was applied to compare adverse events with 95% CrI. The surface under the cumulative ranking area (SUCRA) was calculated to make the ranking of the treatments for outcomes.

Results: Twelve randomized controlled trials (RCTs) were eligible. Compared with placebo, zoledronate (SMDs 2.74, 95% CrI 1.36-4.11) and sodium-fluoride (SMDs 1.23, 95% CrI 0.19-2.26) revealed statistical significance in increasing lumbar spine BMD (LSBMD). According to SUCRA ranking, zoledronate (SUCRA = 2.5%) might have the highest probability to be the best treatment for increasing LSBMD in CD patients among all agents, followed by sodium-fluoride (27%). For safety assessment, the incidence of adverse events (AEs) demonstrated no statistical difference between agents and placebo. The corresponding SUCRA values indicated that risedronate (SUCRA = 77%) might be the most safe medicine for low BMD in CD patients and alendronate ranked the worst (SUCRA = 16%).

Conclusions: Zoledronate might have the highest probability to be the best therapeutic strategy for increasing LSBMD. For the safety assessment, risedronate showed the greatest trend to decrease the risk of AEs. In the future, more RCTs with higher qualities are needed to make head-to-head comparison between 2 or more treatments.

Figure 1

Flow diagram of study selection. A total of 12 studies were included in this network meta-analysis after literature search and selection.

Figure 2

Efficacy and safety of agents in Crohn disease patients with low bone mineral density (BMD): the efficacy was estimated in 2 lower triangle comparing column-defining with row-defining treatments (A, the change of lumbar spine BMD (LSBMD); B, the change of total hip BMD [THBMD]). The efficacy was estimated in upper triangle (A) comparing row-defining with column-defining treatments. For efficacy and safety assessment, treatment effects were summarized as standardized mean difference (SMD) and odds ratio (OR) with their corresponding 95% credible intervals, respectively. For change of BMD, SMD lower than 0 favor the row-defining treatment while for adverse effects, ORs lower than 1 favor the column-defining treatment.

Figure 3

Surface under the cumulative ranking curve expressed as percentages ranking therapeutic effects of treatments for Crohn disease patients with low bone mineral density (BMD). The surface under the cumulative ranking area of each bar represents the probability size of each treatment. The color of the bar represents the specific therapeutic schedule. The abscissa represents the therapeutic probability of various drugs and the ordinate denotes the outcomes about the change of BMD and the incidence of adverse events. For the change of BMD, the pharmacological agent with the longest bar means the most efficacious treatment while agent with the shortest bar indicates the worest one. Oppositely, for the incidence of adverse events, the pharmacological agent with the shortest bar means the most safety treatment while agent with the longest bar indicates the worest one. LSBMD = lumbar spine bone mineral density, THBMD = total hip bone mineral density.

Figure 4

Forest plot with 95% confidence interval (CI) or credible intervals (CrI) (95% CI for direct evidences and CrI for indirect evidences) for continuous variable (change of bone mineral density in lumbar spine) by traditional meta-analysis and Bayesian network meta-analysis. Ale = alendronate, Ris = risedronate, Phy = phylloquinone, Zol = zoledronate, Sod = sodium-fluoride, Iba = ibandronate, Eti = etidronate, Pam = pamidronate, Pla = placebo.