Abaloparatide for risk reduction of nonvertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis

Abstract

Summary This network meta-analysis assessed the efficacy of abaloparatide versus other treatment options to reduce the risk of fractures in women with postmenopausal osteoporosis. The analysis indicates that abaloparatide reduces the risk of fractures in women with postmenopausal osteoporosis versus placebo and compared with other treatment options. Introduction This network meta-analysis (NMA) assessed the relative efficacy of abaloparatide versus other treatments to reduce the risk of fractures in women with postmenopausal osteoporosis (PMO). Methods PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published before December 20, 2017, that included women with PMO who were eligible to receive interventions for primary or secondary fracture prevention. The NMA was conducted by fracture site (vertebral [VF], nonvertebral [NVF], and wrist), with the relative risk (RR) of fracture versus placebo the main clinical endpoint. The NMA used fixed-effects and random-effects approaches. Results A total of 4978 articles were screened, of which 22 were included in the analysis. Compared with other treatments, abaloparatide demonstrated the greatest treatment effect relative to placebo in the VF network (RR = 0.13; 95% credible interval [CrI] 0.04–0.34), the NVF network (RR = 0.50; 95% CrI 0.28–0.85), and the wrist fracture network (RR = 0.39; CrI 0.15–0.90). Treatment ranking showed that abaloparatide had the highest estimated probability of preventing fractures in each of the networks (79% for VF, 70% for NVF, and 53% for wrist fracture) compared with other treatments. Individual networks demonstrated a good level of agreement with direct trial evidence and direct pair-wise comparisons. Conclusions This NMA indicates that abaloparatide reduces the RR of VF, NVF, and wrist fracture in women with PMO with or without prior fracture versus placebo, compared with other treatment options. Limitations include that adverse events and drug costs were not considered, and that generalizability is limited to the trial populations and endpoints included in the NMA. Electronic supplementary material The online version of this article (10.1007/s00198-019-04947-2) contains supplementary material, which is available to authorized users.

Clinical efficacy and safety of drug interventions for primary and secondary prevention of osteoporotic fractures in postmenopausal women: Network meta-analysis followed by factor and cluster analysis

“…(RR 0.32) had greater risk reduction as for vertebral fractures, which supports these three drug treatments with advantage in efficacy. These effect sizes of the four treatments for reducing vertebral and nonvertebral fractures are similar with those estimated in two prior studies [14,15] in which network meta-analyses were performed based on the combined data for primary and secondary prevention of osteoporotic fractures in PMW.…”

“…Their superior efficacy derived from the ability of significantly reducing vertebral fractures (vs. placebo, RRs for abaloparatide and zoledronate: 0.17 and 0.31) and nonvertebral fractures (vs. placebo, HRs for abaloparatide and zoledronate: 0.54 and 0.76). These effect size estimates of abaloparatide and zoledronate approximate to those calculated in three previous studies [14,15,42]. Meanwhile, they significantly or insignificantly increased withdrawals deriving from adverse events (vs. placebo, abaloparatide: RR 1.7, 95% CI 1.2-2.3); zoledronate: RR 1.2, 95% CI 0.83-1.6)), which led to their inferior safety.…”

“…Third, we improved the accuracy of network meta-analysis results by doing the following things: ① an identical drug used at different intervals was taken for different interventions, such as zoledronate (once per 12 months), zoledronate (once per 18 months) and zoledronate (once per 24 months) were considered as three interventions in this study, although alendronate used at a dose of 5 or 10 mg was taken for one intervention because the anti-fracture efficacy of these two dosages was combined in included trials [58,59]; ② we only kept double-blind RCTs for the assessment of comparative acceptability; ③ we used the fixed-effects model to perform network meta-analyses for vertebral fractures and nonvertebral fractures in the primary prevention group, given the presence of only low or no inconsistency and heterogeneity in those analyses; and ④ we synthesized HRs (instead of RRs) for nonvertebral fractures since primary studies had provided study-level survival data for this outcome and survival data contains more information (i.e., the time when an event of interest occurs) than dichotomous data does. Fourth, we further improved the network transitivity in this study compared to prior network meta-analyses [14,15,42] by only considering those trials which mainly enrolled white people given that the majority of participants were Caucasians in those trials of new drug interventions (e.g., zoledronate used once per 18 months [22], romosozumab [50,51], and abaloparatide [43]), by only considering those trials in which all participants were women with primary osteoporosis since those new drug trials [22,43,50,51] completely enrolled this type of patients, and by grouping all trials into the primary prevention subgroup and the secondary prevention subgroup to increase the comparability of baseline characteristics inside each subgroup. This study has some limitations.…”

“…Due to the lack of a randomized controlled trial (RCT) comparing all drug interventions for PMO, the best way of assessing their comparative effectiveness and safety is to perform network meta-analysis using the data deriving from RCTs in which an active drug intervention was compared with placebo or active interventions were compared among them. Although there are several network meta-analyses [14][15][16][17][18][19][20][21] having reported the comparative anti-fracture efficacy of some drug treatments for PMO, none of these studies provided evidence on comparative efficacy respectively for primary prevention and for secondary prevention of PMO. Meanwhile, none of them evaluated a novel drug intervention of zoledronate intravenously used at a dosage of 5 mg per 18 months [22], while none but two [14,15] evaluated two newly approved agents of romosozumab [23] and abaloparatide [24].…”

“…Although there are several network meta-analyses [14][15][16][17][18][19][20][21] having reported the comparative anti-fracture efficacy of some drug treatments for PMO, none of these studies provided evidence on comparative efficacy respectively for primary prevention and for secondary prevention of PMO. Meanwhile, none of them evaluated a novel drug intervention of zoledronate intravenously used at a dosage of 5 mg per 18 months [22], while none but two [14,15] evaluated two newly approved agents of romosozumab [23] and abaloparatide [24]. Furthermore, none of them performed relevant analyses to identify the optimal drug treatment(s) when both efficacy and safety considered, while none but two [16,18] performed analysis on safety outcome.…”