Some text, tables and figures in this chapter have been reproduced from Paskins Z, et al. BMJ Open 2020;10:e040634. https://doi.org/10.1136/bmjopen-2020-040634. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See https://creativecommons.org/licenses/by/4.0/. The text, tables and figures below include minor additions and formatting changes to the original text.
Some text, tables and figures in this chapter have been reproduced from Bastounis A, et al. JBMR Plus 2022;e10620. https://doi.org/10.1002/jbm4.10620. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See https://creativecommons.org/licenses/by/4.0/. The text, tables, figures below include minor additions and formatting changes to the original text.
Some text, tables and figures in this chapter have been reproduced from Bastounis A, et al. Osteoporos Int 2022;33:1223–3. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text, tables and figures below include minor additions and formatting changes to the original text.
Introduction
Bisphosphonates, such as ALN, risedronate (RIS), IBN and IV ZOL, have been found to be effective in reducing the risk of osteoporotic fragility fractures.2 However, there is no conclusive evidence regarding their comparative effectiveness in specific patient groups, such as patients with low bone mineral density (BMD).97 This can be accounted for by the paucity of comparative trials that would provide insight on how BP works through time in the light of adverse events associated with the use of BP. There is a need, therefore, to undertake a comparative evaluation of BP, testing their effectiveness in reducing the risk of fragility fractures. Adherence to BP is crucial to realise clinical benefits and reduce the risk of fractures; however, recent studies suggest that adherence to oral and parenteral BP is suboptimal and tends to decrease over time.98,99 Adherence could be conceived as an umbrella term which encompasses the following terms: (1) initiation, (2) implementation and (3) discontinuation of treatment.100,101 Initiation of treatment refers to the time when people start a prescribed medication (i.e. receive the first dose of a prescribed medication), implementation refers to the level of compliance to the dosing regimen of a prescribed medication from the first to the last dose and discontinuation refers to the time when people stop taking their prescribed medication.102
The aim of this chapter was to conduct two systematic reviews with NMAs to explore treatment effectiveness and treatment adherence. The treatment effectiveness systematic review was an update of a systematic review that was previously published as part of a NICE HTA report45 but also included an update of the estimates regarding the comparative effectiveness of the BP to inform an economic evaluation regarding BP benefit-to-risk ratio. NMA techniques are particularly well suited in the context of pharmacological interventions when we seek to compare three or more interventions simultaneously, combining both direct and indirect evidence across different networks of studies.103 NMA can be performed either by adopting a Bayesian approach104 or by a frequentist approach.105 In these NMAs, a Bayesian approach was followed as it is well suited for informing the cost-effectiveness analysis. The second systematic review sought to provide estimates regarding users’ probability to adherence in BPs’ treatment, exploring patterns of discontinuation, persistence and compliance among people with different clinical profiles.
Methods
Both systematic reviews were registered with PROSPERO (updated review: CRD42020177155; adherence review: CRD42020177166) and reported following the PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-Analyses of Health Care Interventions checklist.106
Eligibility criteria
The eligibility criteria of both reviews regarding the population and interventions of interest were the same and have been described elsewhere.92 Only studies in which the interventions of interest (ALN, IBN-IV, IBN-oral, RIS and ZOL) were assessed within their licensed doses for treating osteoporosis. Studies that reported data for both licensed and unlicensed dose study groups were considered eligible only if data for the licensed groups were separately reported. Studies reporting comparisons among the interventions of interest were considered eligible for inclusion. In the updated review, we targeted the following outcomes: fragility fractures, BMD at the femoral neck, mortality, adverse effects and health-related quality of life (HRQoL), with only randomised controlled trials (RCTs) eligible for inclusion. In the adherence review, the outcomes of interest were persistence and compliance, quantified either as continuous (e.g. absolute numbers or rates) or discrete measures (e.g. absolute number of participants being persistent/compliant based on pre-specified thresholds). In this review, RCTs, non-randomised parallel comparative studies and observational (both prospective and retrospective) studies were considered eligible for inclusion. In the RCTs, persistence was indirectly inferred by assessing the total number of participants who dropped out at 12 and 24 months; in the observational studies, persistence was inferred by assessing the total number of participants who discontinued their treatment based on treatment refill gaps, using data from claim databases or medical records. In the observational studies, compliance was indirectly measured by assessing ‘treatment continuity’ and using percentages/absolute numbers of medication possession ratios (MPR) and number of users with MPRs over a pre-specified threshold. Reports published as abstracts or conference presentations were excluded where insufficient details were reported. RCTs which were judged otherwise eligible but did not report outcome data per treatment arm or reported zero dropouts for both arms were excluded. Studies which reported the outcomes of interest for BP groups collapsed or studies reporting comparisons based solely on the frequency of administration (e.g. daily vs. weekly) were also excluded.
Search strategy and information sources
A set of comprehensive search strategies were undertaken to systematically identify eligible studies in both systematic reviews. The search strategies comprised the following main elements: searching of electronic databases (including unpublished data and trial registries), extensive keyword hand-searching and scrutiny of bibliographies of retrieved papers.
The following databases were searched in both reviews:
- MEDLINE® In-Process and Other Non-Indexed Citations and MEDLINE (Ovid), including PubMed
- EMBASE (Ovid)
- Cochrane Database of Systematic Reviews (Wiley Interscience)
- Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Interscience)
- Cumulative Index to Nursing and Allied Health Literature (CINAHL, EBSCO)
- Database of Abstract of Reviews of Effects (Wiley Online Library)
- HTA Database (CRD Database)
- NHS Economic Evaluation Database (CRD Database)
- OpenGrey
- Science Citation Index (ISI Web of Knowledge)
- CPCI – Science (Web of Science)
- ClinicalTrials.gov.
Searches of the updated review covered the period from September 2014 to 1 March 2021. Searches of the adherence review covered the period from January 2000 to 25–26 March 2021. In both reviews, all potentially relevant citations were downloaded to Endnote X8 Reference Manager bibliographic software (version 8.0; Clarivate Analytics, Philadelphia, PA, USA).
Study selection, data collection process and data items
Selected studies were imported into Rayyan online software.107 Two independent reviewers screened studies for relevance based on titles/abstracts and later full texts (AB and TL) with disagreements resolved through discussion or by consulting a third reviewer (JLB/OS). Two independent reviewers (AB, TL) conducted full-text screening with a high level of agreement observed in both reviews (κ = 0.91 in the update review and κ = 0.84 in the adherence review). A standardised and pilot-tested data extraction form was used to extract relevant data in both reviews. One reviewer (AB) extracted data, with a second reviewer (TL) independently checking at least 50% and 80% of the extracted records in the updated and adherence review, respectively. Data extracted consisted of the following categories: (1) descriptive statistics (e.g. number recruited and randomised, participants’ characteristics); (2) baseline data on outcomes of interest (e.g. comorbidities, fractures at baseline, alcohol use, number of falls); (3) moderators of action [e.g. glucocorticoids (GC) use, patients with osteoporosis, history of fractures/fractures at baseline]; (4) intervention characteristics (e.g. drug type, administration mode, concomitant treatments) and (5) statistics and relevant data on the outcomes of interest expressed either as continuous or binary outcomes [clinical outcomes such as fractures, BMD changes, HRQoL, adverse events mortality, number of participants who dropped out from RCTs, number of users who discontinued with BP treatment, number of users with varying compliance levels based on pre-specified thresholds, mean/range MPR, mean number of infusions/tablet counts, proportion of days covered (PDC) percentage, mean duration of BP treatment]. Authors were contacted when there was lack of data on outcomes of interest and/or further information was needed in order to attest eligibility of relevant studies.
Geometry of networks
Both treatment-placebo (PLB) and treatment-active comparisons were examined, and network plots were created for all outcomes. In both reviews, nodes indicate the different treatments included in the analysis, and thickness of edges connecting the nodes indicates the number of studies informing each comparison (thicker lines indicate more populated comparisons). In the adherence review, node size indicates the number of studies included in each node, and thickness of lines indicates the overall sample size informing each comparison (thicker edges indicate more populated pairwise comparisons).
Risk of bias within individual studies
The methodological quality of the included RCTs was independently assessed at the study level by two reviewers (AB, JLB) using the Cochrane Collaboration risk of bias tool 1.0 (94). The Cochrane Collaboration risk of bias tool 1.0 addresses the following specific domains: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment and incomplete outcome data and selective outcome reporting. Studies were rated with a low risk of bias in the randomisation sequence if they provided an explicit statement on how they performed the randomisation. Open-label trials were rated as high risk in the ‘blinding’ category, whereas higher than 20% attrition at 12 months’ follow-up resulted in high-risk rating in the ‘incomplete outcome data’ category. The methodological quality of the included observational studies was independently assessed at the study level by one reviewer (AB), with a second reviewer (JLB) independently checking 50% of the included studies. Any disagreements were resolved through discussion. The assessment of methodological quality in observational studies was undertaken using the Cochrane Collaboration Risk Of Bias In Nonrandomised Studies of Interventions tool (ROBINS-I).108 Risk-of-bias plots were created by using the ‘robvis’ tool.104
Summary measures and methods of analysis
Updated review
Fractures, mortality and adverse events were reported in a binary form (number of participants experiencing at least one event out of the total number of participants). The data generation process followed a binomial likelihood, assuming an underlying Poisson process for each trial arm. The complementary log–log link function was used to model the NMAs for the binary outcomes.109 Log hazard ratios (HRs) were estimated from the median and corresponding 95% credibility intervals (CrIs) from the 2.5th and 97.5th centiles of the posterior distribution. Treatment ranking probabilities for all fracture outcomes were reported. Changes in BMD were reported as percentage changes per arm from baseline [mean percentage difference per arm plus standard error (SE) of the mean (SE)]. The data generation process followed a normal likelihood. The identity link function was used to model the NMA for BMD change, including study duration as a trial-level covariate and assuming an equal interaction effect between treatments and reference treatment one.110 The treatment effects represented the mean difference (MD) between the percentage change in the treatment group and the comparator group. Mean percentage difference plus 95% CrI were estimated from the posterior distribution. Treatment ranking probabilities and surface under the cumulative ranking (SUCRA) were reported for the BMD data.111
Two different modelling strategies were considered for the treatment effects: (1) a standard, independent random (treatment)-effects model112 was fitted for assessing the comparative effectiveness of BPs in increasing femoral neck BMD and (2) exchangeable treatment-effects models (i.e. effects model where the treatment effects are assumed to arise from a common distribution according to the class of drug)113,114 were fitted for assessing the comparative effectiveness of BPs in preventing fractures, deaths and adverse events, given the relative paucity of data in the aforementioned variables. For BMD changes, the model was completed by using conventional reference prior distributions: (1) trial-specific baseline, μi ~ N(0, 1002); (2) treatment effects relative to reference treatment, d1k ~ N(0, 1002) and (3) between-study standard deviation (SD) of treatment effects, τ ~ U(0, 5). Due to the paucity of data, we used a weakly informative prior distribution for the between-study SD [i.e. τ ~ half-normal HN(0, 0.322)] for the NMAs of hip and wrist fractures and specific-type adverse events (i.e. influenza-like symptoms, myalgia, nasopharyngitis and headache). Based on clinical plausibility, a weakly informative prior distribution for the between-study SD [i.e. τ ~ half-normal HN(0, 0.322)] was used for the NMA of mortality data. All analyses were conducted using OpenBUGS (MRC Biostatistics Unit, Cambridge, UK) and R Studio (R version 4.0.3), using the ‘gemtc’ and ‘rjags’ packages. Convergence to the target posterior distributions was assessed using the Gelman–Rubin statistic for three independent chains with different initial values. For all outcomes, results were based on three independent chains of initial values and 105,000 iterations after a burn-in of 50,000 iterations. Most of NMAs exhibited moderate correlation between successive iterations of the Markov chain, so they were thinned by retaining every 10th sample.
Adherence review
In RCTs, the number of dropouts at 12 and 24 months was reported in a binary form (number of participants who dropped out subtracted from the total number of participants per arm). The data generation process was assumed to follow a binomial likelihood, while NMAs were modelled using the logit function. Log odds ratios (ORs) were estimated from the median and corresponding 95% CrI from the 2.5th and 97.5th centiles of the posterior distribution. In retrospective observational studies, discontinuation was reported in a binary form (number of participants who discontinued the treatment, as this is indicated by pre-specified refill gaps). Given the absence of control conditions in retrospective observational cohorts, ALN was used as the reference treatment. The data generation process was assumed to follow a binomial likelihood. To account for different trial durations, an underlying Poisson process was assumed for each trial arm. The probabilities of any of the aforementioned binary outcomes were considered non-linear functions of event rates, so we modelled the NMAs for the binary outcomes using the complementary log–log link function. Log HRs were estimated from the median and corresponding 95% CrI from the 2.5th and 97.5th centiles of the posterior distribution. Treatment ranking probabilities and SUCRA were also reported.111 For studies including ZOL users, meaningful (> 12-month) follow-up assessments were selected and included in the NMA. In case, there was a follow-up assessment at 12 months only, ZOL arms were excluded from the NMA. For those observational studies which were not included in the discontinuation NMA, effect sizes of discontinuation or persistence were summarised using the vote-counting synthesis method based on the direction of effects.115 Similarly, data on compliance drawn from both RCTs and observational studies were summarised based on the vote-counting synthesis method. Findings from both syntheses are presented using cross-study visual displays.116
Assessment of inconsistency
Consistency of evidence for the NMAs of RCTs was assessed using the node-splitting method117–119 in R Studio (R version 4.0.3). Differences between direct and indirect evidence in all network loops were calculated, with p values < 0.05 indicating the presence of significant inconsistency. In the case of fracture data, inconsistency was assessed for vertebral fractures only. For non-vertebral fractures, no indirect evidence was available. For hip fractures, an assessment of inconsistency was not performed because the direct evidence between ALN and RIS was provided by one small, and unbalanced in terms of sample size, study with zero events in one arm. For wrist fractures, an assessment of inconsistency was not performed because the direct evidence between ALN and RIS was provided by the same small study, and the only direct evidence between ALN and oral IBN-oral was provided by the only three-arm study included in the NMA. For BMD data, the assessment of inconsistency was performed after excluding an outlier study, which was the only study informing the direct relationship between ZOL and ALN, and the three-arm study, which was the only study providing direct evidence for the relationship between RIS and IBN-oral. For the overall adverse event outcome, an assessment of inconsistency was not formally performed because the fit of the model with the data was poor. For myalgia, headache and pyrexia, assessment of inconsistency was not performed because there was no indirect evidence. For influenza-like symptoms, an assessment of inconsistency was not performed because there was only one small study with zero events in the control arm informing the direct relationship between IBN-oral and PLB and three small studies with zero events in control arms informing the direct relationship between ZOL and PLB. Due to the multiple arms reported per study in retrospective observational studies included in the adherence review, a formal assessment of inconsistency in persistence NMA was not performed.
Credibility of the findings
Credibility of findings on persistence was assessed in RCTs only by following the confidence in network meta-analysis (CINeMA) approach,120 where the credibility of findings is accounted for by the assessment of: (1) within-study bias, (2) reporting bias, (3) indirectness, (4) imprecision, (5) heterogeneity and (6) incoherence. In this NMA, HR/OR ranging from 0.8 to 1.25 was used to indicate clinical significance in binary outcomes, while a MD of 2.71 (1/2 SD of baseline control arms) was used to indicate clinical significance in the continuous outcomes (i.e. BMD femoral neck). CINeMA’s freely available web application121 was used to assess credibility of the findings.
Results
Updated review
A PRISMA flow diagram shows the selection of papers for inclusion and exclusion in the updated systematic review (Figure 4). A total of 6623 articles were retrieved, of which 1889 were duplicates. Overall, 4535 studies were excluded following title and abstract screening, and 170 were excluded following full-text screening. Data from 25 newly identified trials obtained from 29 published reports were added to the data obtained from 43 trials identified in the previous review (92) resulting in a total of 68 trials out of 47,007 participants.
FIGURE 4 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the selected studies in the updated review. Reproduced from Bastounis A, et al. JBMR Plus 6:e10620. https://doi.org/10.1002/jbm4.10620. (Figure not reproduced here; see the original article.)
Network structures and geometry
Four networks were created for fracture data. Data for vertebral and hip fractures provided us with one closed loop of evidence. Data for non-vertebral fractures did not provide us with a closed loop of evidence, and the indirect effects were drawn from a single study. Similarly, data for wrist fractures provided us with a single loop after removing the only three-arm study of the network. Data for BMD provided us with five closed loops after removing the single three-arm study, whereas three of the loops were accounted for by single studies. A total of 28,340 (nstudies = 27) participants received BPs (ntreatments = 5) to prevent vertebral fractures. The most commonly studied treatments were ZOL (n = 10) and RIS (n = 10). PLB was used as the comparator arm in 24 studies. The most frequently used comparisons were ZOL versus PLB (n = 9) and RIS versus PLB (n = 8). A total of 26,435 (nstudies = 19) received BPs (ntreatments = 5) for preventing non-vertebral fractures. The drug that was more commonly studied was ZOL (n = 7). PLB was used as the comparator arm in 18 studies. The most commonly studied comparisons were ZOL versus PLB (n = 7) and ALN versus PLB (n = 6). A total of 28,570 (nstudies = 44) participants received BPs (ntreatments = 5), providing us with data for femoral neck BMD. Data were drawn from 43 two-arm studies and 1 three-arm study. The studied medications were more commonly ALN (nstudies = 23) and RIS (nstudies = 16). PLB was used as the comparator arm in 37 studies. The most commonly studied comparisons were ALN versus PLB (n = 17 studies) and RIS versus PLB (n = 11 studies). No trials testing IBN-IV against any of the aforementioned BPs were identified.
Characteristics of studies and risk of bias within individual studies
Of the 25 new trials of 6318 participants identified from 29 published reports, covering the period from 2014 to 2021, 10 studies were conducted in China,122–131 5 studies were conducted in Europe,132–136 3 were conducted in the USA,137–139 3 were conducted in Oceania,140–142 1 in Japan,143 1 in South Korea144 and 2 were conducted internationally.145,146 Four extensions of original trials147–150 and one ancillary substudy of a main trial137 were available, accounting for the total number of eligible studies identified. In two cases,134,141 trials published before 2014 were deemed eligible for inclusion and included in the updated review after receiving clinicians’ feedback. The sample sizes of the trials identified in the updated review ranged from 30 to 2000 participants.
Overall, 19 trials recruited exclusively female participants. In nine trials, most of the participants had received a diagnosis of osteoporosis before entering the study, participants in nine trials fulfilled the criteria for secondary causes of osteoporosis and participants in four trials received the treatments of interest post operation, whereas the majority of participants had a history of fractures or were recruited on the basis of fractures at baseline in six trials. Overall, 15 trials identified in the updated review provided us with data regarding the occurrence of fractures, whereas 13 trials provided data regarding percentage BMD change at the femoral neck and 3 provided data regarding absolute BMD changes. All but two of the newly identified trials reported prevalence of adverse events. In total, the overall risk of bias was high in 12 trials. Most of the high-risk ratings were observed in the ‘blinding of participants and personnel’ and ‘incomplete outcome data’ domains.
Synthesis of results on the main outcomes (updated review)
Primary outcome: vertebral fractures
Data were available from 27 RCTs. The model fitted the data relatively well [data points: 54; total residual deviance (Dres): 56.34; deviance information criterion (DIC): 298.5]. The between-study SD was estimated to be 0.18 (95% CrI 0.01 to 0.46), whereas the between-treatment SD was estimated to be 0.19 (95% CrI 0.01 to 0.46). All treatments were associated with beneficial treatment effects relative to PLB, and all treatment effects were statistically significant (p < 0.05) (Table 8). ZOL, ALN and RIS were also found to exert clinically significant effects. ZOL was associated with the greatest effect (HR 0.38; 95% CrI 0.28 to 0.49) and was most likely to be the most effective treatment (probability: 0.55).
| ZOL | 3.80 (2.07 to 4.80) | ZOL | 0.33 (0.23 to 0.43) | RIS | - | |||||||||||
| 1.15 (0.24 to 2.08) | ALN | 3.10 (2.40 to 3.80) | 0.88 (0.58 to 1.21) | ALN | 0.43 (0.33 to 0.53) | 0.98 (0.82 to 1.35) | ZOL | - | ||||||||
| 1.31 (−0.08 to 2.73) | 0.15 (−1.00 to 1.32) | IBN-oral | 2.30 (0.21 to 4.30) | 0.87 (0.37 to 1.82) | 0.99 (0.47 to 2.18) | IBN-oral | - | 0.95 (0.50 to 1.33) | 0.98 (0.55 to 1.36) | IBN-oral | - | |||||
| 1.76 (0.82 to 2.74) | 0.6 (−0.09 to 1.31) | 0.45 (−0.80 to 1.72) | RIS | 2.40 (1.05 to 3.30) | 0.76 (0.50 to 1.07) | 0.88 (0.6 to 1.22) | 0.91 (0.37 to 1.82) | RIS | 0.54 (0.39 to 0.69) | 0.92 (0.65 to 1.11) | 0.93 (0.74 to 1.11) | 0.99 (0.63. 1.5) | ALN | - | ||
| 4.02 (3.20 to 4.84) | 2.86 (2.37 to 3.36) | 2.70 (1.56 to 3.86) | 2.25 (1.61 to 2.87) | PLB | 0.38 (0.28 to 0.49) | 0.44 (0.33 to 0.57) | 0.44 (0.02 to 0.94) | 0.50 (0.37 to 0.66) | PLB | 0.70 (0.53 to 0.84) | 0.71 (0.61 to 0.81) | 0.75 (0.51 to 1.26) | 0.77 (0.63 to 0.91) | PLB |
Primary outcome: non-vertebral fractures
Data were available from 19 RCTs. The model fitted the data well (data points: 38; Dres: 28.57; DIC: 224.8). The between-study SD was estimated to be 0.08 (95% CrI 0.06 to 0.24), whereas the between-treatment SD was estimated to be 0.21 (95% CrI 0.005 to 0.99). All treatments were associated with beneficial treatment effects relative to PLB, with RIS, ALN and ZOL being statistically significant (p < 0.05) (see Table 8). RIS was associated with the greatest effect (HR 0.7; 95% CrI 0.53 to 0.84) and was most likely to be the most effective treatment (probability: 0.44). ZOL was found to be comparably effective, showing more precise effects (HR 0.71; 95% CrI 0.61 to 0.81).
Primary outcomes: hip fractures and wrist fractures
Data on the occurrence of hip fractures were available from 14 RCTs. The model fitted the data well (data points: 28; Dres: 22.22; DIC: 144.8). The between-study SD was estimated to be 0.1 (95% CrI 0 to 0.33), whereas the between-treatment SD was estimated to be 0.36 (95% CrI 0 to 1.8). All treatments were associated with beneficial treatment effects relative to PLB, whereas ZOL, ALN and RIS were found to exert statistically significant treatment effects (p < 0.05). ZOL (HR 0.61; 95% CrI 0.47 to 0.79) and ALN (HR 0.61; 95% CrI 0.4 to 0.86) were associated with the greatest effects, with the effects of the former being clinically significant. Data on the occurrence of wrist fractures were available from 10 RCTs, with one RCT comparing three treatments. The model fitted the data well (data points: 21; Dres: 21.83; DIC: 95.26). The between-study SD was estimated to be 0.29 (95% CrI 0 to 0.68), whereas the between-treatment SD was estimated to be 0.44 (95% CrI 0.01 to 1.8). All treatments were associated with beneficial treatment effects relative to PLB, although the treatment effects were not statistically significant (p > 0.05). ZOL was associated with the greatest effect, with HR 0.54 (95% CrI 0.04 to 1.36) and was most likely to be the most effective treatment (probability: 0.47).
Outline of results on the secondary outcomes
Eleven NMAs were conducted on secondary outcomes (Appendix 1, Figure 13). ZOL was found to be significantly worse compared to PLB on overall adverse events (HR 1.52; 95% CrI 1.19 to 1.96), arthralgia (HR 1.95; 95% CrI 1.17 to 3.01), headache (HR 2.76; 95% CrI 2.32 to 3.29), influenza-like symptoms (HR 6.05; 95% CrI 3.07 to 10.86), myalgia (HR 5.21; 95% CrI 4.35 to 6.3) and pyrexia symptoms (HR 9.37; 95% CrI 7.11 to 15.56). The model fit with the data was poor on overall adverse-events outcome (Dres: 91.23; data points: 77), good on arthralgia outcome (Dres: 31.98; data points: 32), moderate on headache outcome (Dres: 25.46; data points: 22), poor on influenza-like symptoms outcome (Dres: 35.93; data points: 24), relatively good on myalgia outcome (Dres: 24.69; data points: 22) and moderate on pyrexia outcome (Dres: 27.27; data points: 24).
Risk of bias across studies and credibility of findings
Risk-of-bias assessment at outcome level was undertaken for all studies conferring data on vertebral fractures and BMD. For vertebral fractures, most of the major concerns were detected in the comparisons of RIS versus PLB (> 70%) and ALN versus RIS (> 40%), with the former being informed by eight direct comparisons and the latter by one direct comparison. From mixed treatment comparisons, findings drawn from two treatment PLB comparisons were rated as highly credible (ALN vs. PLB; ZOL vs. PLB). Findings drawn from RIS versus PLB and RIS versus ZOL comparisons were considered of moderate credibility, with the latter being informed by only one direct pairwise comparison. Findings drawn from ALN versus IBN-oral and ALN versus RIS comparisons were considered of low credibility, with the former comparison being informed by a small study of zero events in the control group. From indirect comparisons, evidence drawn from the treatment–PLB comparison (PLB vs. IBN-oral) and one active comparison (ALN vs. ZOL) were both rated as highly credible, whereas the rest of the indirect comparisons produced evidence of low credibility. For percentage BMD change, most of the major concerns were detected in the active comparison of ALN versus RIS (marginally > 10%), with four studies providing evidence. Proportion of evidence drawn from studies with major concerns was < 10% in the rest of the comparisons. Apart from two active comparisons (ALN vs. ZOL; IBN-oral vs. ZOL), all the comparisons provided us with highly credible findings. With regard to the two comparisons providing us with evidence of low credibility, the direct evidence for the comparison of ALN versus ZOL was drawn from a single, outlier study.
Adherence review
A PRISMA flow diagram (Figure 5) shows the selection of papers for inclusion and exclusion. A total of 10,030 articles were retrieved, of which 1729 were duplicates. Overall, 7976 studies were excluded following title and abstract screening, and 220 were excluded following the full-text screen. Data were extracted from 59 RCTs drawn from 69 published reports and 43 observational studies drawn from 45 published reports, resulting in a total population of 2,656,659 participants. Table 9 lists all the studies (see Appendix 2 list of references).
FIGURE 5 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the selected studies in the adherence review. Reproduced from Bastounis A, et al. Osteoporos Int 2022;33(6):1223–3. https://doi.org/10.1007/s00198-022-06350-w. Epub 21 February 2022. PMID: 35188591; PMCID: PMC9106630. (Figure not reproduced here; see the original article.)
| Study IDReference list included as an appendix | Study design | Country | Na/gender (%)/age (mean, SD)b | % patients with prior incidence of fractures | Drugs | Dose/mode/frequency | % GC users | % patients with (PM) OP | Compliance | Persistence/discontinuation |
|---|---|---|---|---|---|---|---|---|---|---|
| Adachi et al., 2009 | RCT | Canada and Colombia | 438/F (100)/ALN: 65.4 (10.5); PLB: 65.7 (9.9) | P (6.8) | ALN; PLB | 10 mg/oral/daily | NR | NR | NR | Discontinuation (n/N, total), 3 months ALN: 54/291 PLB: 17/147 Discontinuation due to AEs (n/N, total), 3 months ALN: 39/291 PLB: 14/147 Discontinuation due to other reasons (n/N, total), 3 months ALN: 15/291 PLB: 3/147 |
| Adami et al., 2020 | Retr. | USA | 73,800/F (100)/NR | P (NR) | ALN; RIS; ZOL | NR/oral; IV/NR | P (NR) | P (NR) | NR | Discontinuation (n/N, %), ≈24 months ALN: 20,455/59,251, 34.5% RIS: 2388/6806, 35.1% ZOL: 3438/7743, 44.4% |
| Bala et al., 2014 | RCT | NR | 163/F (100)/RIS: 62 (6); PLB: 61 (4) | NR | RIS; PLB | 35 mg/oral/weekly | NP | NP | NR | Discontinuation (n/N, total), 12 months RIS: 9/109 PLB: 2/54 Discontinuation due to AEs (n/N, total), 12 months RIS: 4/109 PLB: 0/54 Discontinuation due to other reasons (n/N, total), 12 months RIS: 5/109 PLB: 2/54 |
| Belhassen et al., 2017 | Retr. | France | 946/NR/NR | NR | ALN; IBN; RIS; ZOL | NR | NR | NR | NR | Persistence (refill gap ≥ 12 months): 12 months: ALN: 328/453 (72.4%); IBN: 148/182 (81.3%); RIS: 236/310 (76.1%); ZOL: 1/1 24 months: ALN: 252/453 (55.6%); IBN: 117/182 (64.3%); RIS: 176/310 (56.8%); ZOL: 0 36 months: ALN: 218/453 (48.1%); IBN: 92/182 (50.5%); RIS: 152/310 (49%); ZOL: 0 48 months: ALN: 196/453 (43.3%); IBN: 76/182 (41.8%); RIS: 131/310 (42.3%); ZOL: 0 60 months; ALN: 159/453 (35.1%); IBN: 0; RIS: 100/310 (32.3%); ZOL: 0 Median discontinuation (years): ALN: 1; IBN: 1.9; RIS: 1.2; ZOL: 1 Discontinuation (without any switch): ALN: 177/453; IBN: 79/182; RIS: 130/310; ZOL: 1 |
| Berecki-Gisolf et al., 2008 | Retr. | Australia | 756/F (100)/80 (5.94) | NR | ALN; RIS | 70 mg (ALN); 35 mg (RIS)/oral/weekly | NR | P (100) | NR | Persistence failure ALN (ref.) vs. RIS (refill gap ≥ half the prescription duration) HR = 1.19 (95% CI 0.98 to 1.46); p = 0.09 |
| Black et al., 2007 (Ext.) Black et al., 2012 Black et al., 2015 (HORIZON) | RCT | Multicentre (USA; Australia; Argentina; Belgium; Canada; Colombia; Finland; France; Germany; Hong-Kong; Hungary; Italy; New Zealand; Norway; Poland; Sweden; Switzerland; Thailand) | 7765/F (100)/ZOL: 78 (4.71); PLB: 78.1 (4.85) | P (NR) | ZOL; PLB | 5 mg/IV/annually | NP | P (100) | Compliance 100% (n/N, per infusion), 36 months ZOL: 3086/3875 PLB: 3174/3861 Compliance 66.6% (n/N, per infusion), 36 months ZOL: 344/3875 PLB: 359/3861 Compliance 33.3% (n/N, per infusion), 36 months ZOL: 432/3875 PLB: 319/3861 | Discontinuation (n/N, total), 36 months ZOL: 641/3876 PLB: 607/3889 Discontinuation due to AEs (n/N, total), 36 months ZOL: 80/3876 PLB: 70/3889 Discontinuation (n/N, total), 108 months ZOL: 21/95 PLB: 18/95 Discontinuation due to AEs (n/N, total), 108 months ZOL: 2/95 PLB: 1/95 Discontinuation due to other reasons (n/N, total), 108 months ZOL: 19/95 PLB: 17/95 |
| Bone et al., 2000 | RCT | USA | 142/F (100)/ALN: 61 (8); PLB: 62 (9) | NR | ALN; PLB | 10 mg/oral/daily | NR | P (100) | NR | Discontinuation (n/N, total), 24 months ALN: 24/92 PLB: 16/50 Discontinuation due to AEs (n/N, total), 24 months ALN: 6/92 PLB: 5/50 Discontinuation due to other reasons (n/N, total), 24 months ALN: 18/92 PLB: 11/50 |
| Bonnick et al., 2006 Extension of Rosen et al., 2005 (FACT) | RCT | USA | 1053/F (100)/64.4 (9.5) | NR | ALN; RIS | 70 mg; 35 mg/oral/weekly | NP | P (100) | NR | Discontinuation (n/N, total), 12 months ALN: 82/520 RIS: 79/533 Discontinuation due to AEs (n/N, total), 12 months ALN: 33/520 RIS: 33/533 Discontinuation due to other reasons (n/N, total), 12 months ALN: 49/520 RIS: 46/533 Persistence (n/N), 24 months ALN: 375/411 RIS: 375/414 |
| Boonen et al., 2012 | RCT | Europe, South America, Africa, Australia | 1199/F (0)/67 (26) | P (NR) | ZOL; PLB | 5 mg/IV/annually | NP | NA | Number not receiving the 2nd infusion (n/N, %) ZOL: 52/588 (8.8%) PLB: 53/611 (8.7%) | Discontinuation (n/N, total), 24 months ZOL: 58/588 PLB: 71/611 Discontinuation due to AEs (n/N), 24 months ZOL: 11/588 PLB: 11/611 Discontinuation due to other reasons (n/N), 24 months ZOL: 39/588 PLB: 60/611 |
| Boonen et al., 2009 | RCT | Europe, Lebanon, Australia, USA | 284/F (0)/RIS: 60 (11); PLB: 62 (11) | P (NR) | RIS; PLB | 35 mg/oral/weekly | P (100) | NA | Compliance (%) RIS: 98 PLB: 91 | Discontinuation (n/N, total), 24 months RIS: 16/191 PLB: 18/93 Discontinuation due to AEs (n/N, total), 24 months RIS: 7/191 PLB: 9/93 Discontinuation due to other reasons (n/N, total), 24 months RIS: 9/191 PLB: 9/93 |
| Calabria et al., 2016 | Retr. | Italy | 40,003/F (88.25)/71 (10) | NR | ALN; RIS | 70 mg (ALN); 35 mg (RIS)/oral/weekly | P (NR) | NR | MPR ≥ 80% (6 months): ALN: 8029/15,521 (51.7%) ALN and chol.: 5826/10,485 (55.6%) RIS: 7836/13,997 (56%) MPR ≥ 80% (12 months): ALN: 6855/15,521 (44.2%) ALN and chol.: 5005/10,485 (47.7%) RIS: 6715/13,997 (48%) MPR ≥ 80% (36 months): ALN: 4952/15,521 (31.9%) ALN and chol.: 3540/10,485 (33.8%) RIS: 4880/13,997 (34.9%) | NR |
| Carbonell-Abella et al., 2015 | Retr. | Spain | 127,722/F (77.5)/66.9 (11) | NR | ALN; RIS; IBN-oral | 70 mg, 10 mg (ALN); 5 mg, 35 mg (RIS); 150 mg (IBN)/oral/daily; weekly; monthly | NR | NR | NR | Discontinuation, SHR (95% CI) (filling gap ≥ 6 months) ALN (weekly): ref. ALN (daily): HR = 1.64 (95% CI 1.52 to 1.76) RIS (daily): HR = 1.86 (95% CI 1.74 to 1.99) RIS (weekly): HR = 1.12 (95% CI 1.10 to 1.14) IBN (monthly): HR = 1.06 (95% CI 1.04 to 1.08) Discontinuation (filling gap ≥ 12 months): ALN (weekly): ref. |
| ALN (daily): HR = 1.74 (95% CI 1.61 to 1.88) RIS (daily): HR = 1.98 (95% CI 1.84 to 2.12) RIS (weekly): HR = 1.15 (95% CI 1.13 to 1.17) IBN (monthly): HR = 1.11 (95% CI 1.09 to 1.14) Persistence 12 months: ALN (weekly): 22,012/55,117 ALN (daily): 70/497 IBN (monthly): 4750/13,270 RIS (weekly): 7892/25,312 RIS (daily): 33/430 | ||||||||||
| Cheen et al., 2012 | Retr. | Singapore | 798/F (92)/68.5 (10.8) | P (47.1) | ALN; RIS | NR/oral/daily; weekly | NR | NR | Mean MPR 24 months (%, SD, n) ALN: 79.3 (27.6%), n = 497, p = 0.67 RIS: 78.3 (27.3%), n = 301 MPR ≥ 80% (24 months) ALN: 66%, n = 497, p = 0.13 RIS: 60.8%, n = 301 | Mean persistence 12 months (n/N, %, 30-day refill gap) ALN: 352/497 (70.8%) RIS: 199/301 (66.1%) |
| Cheng et al., 2015 | Retr. | USA | 8495/F (100)/66.2 (11.5) | P (13.6); 13 (ALN); 11.6 (IBN); 12 (RIS) | ALN; IBN; RIS | NR/oral/NR; monthly | NR | P (35.8); 22.2 (ALN); 46.8 (IBN); 35.3 (RIS) | MCR ≥ 80% (12 months) ALN (n = 5458): 31.3% IBN (n = 1696): 30.4% RIS (n = 1341): 25.6% Weight-adjusted compliance 12 months (women aged ≥ 50 and increased risk of fracture, 60-day refill gap) ALN (n = 2820): 32.8% IBN (n = 1062): 30.1% RIS (n = 716): 25% | Persistence (12 months, 60-day refill gap) ALN: 1916/5458 (35.1%) IBN: 573/1696 (33.8%) RIS: 388/1341 (28.9%) Weight-adjusted persistence 12 months (%) ALN: 35.1 IBN: 33.8 RIS: 28.9 Weight-adjusted persistence 12 months (women aged ≥ 50 and increased risk of fracture, 60-day refill gap) ALN (n = 2820): 36% IBN (n = 1062): 33.4% RIS (n = 716): 28% |
| Cheung et al., 2020 | RCT | Australia | 76/F (0)/ZOL: 68.3 (7.77); PLB: 69 (7.01) | P (NR) | ZOL; PLB | 5 mg/IV/annually | NP (95% received ADT) | NR | NR | Discontinuation (n/N), 12 months ZOL: 4/39 PLB: 11/37 Discontinuation (n/N), 24 months ZOL: 13/39 PLB: 15/37 |
| Cosman et al., 2016 | RCT | USA | 175/F (100)/ALN: 66.9 (7.5); PLB: 67.8 (7.8) | P (NR) | ALN; PLB | 70 mg/oral/weekly | NP | P (100) | NR | Discontinuation (n/N, total), 12 months ALN: 19/87 PLB: 20/88 Discontinuation due to AEs (n/N), 12 months ALN: 3/87 PLB: 6/88 Discontinuation due to other reasons (n/N), 12 months ALN: 16/87 PLB: 14/88 |
| Cryer et al., 2005 | RCT | USA | 454/F (100)/ALN: 64.6 (10); PLB: 65.8 (9.9) | NP | ALN; PLB | 70 mg/oral/weekly | NP | P (100) | NR | Discontinuation (n/N, total), 6 months ALN: 31/224 PLB: 31/230 Discontinuation due to AEs (n/N), 6 months ALN: 10/224 PLB: 20/230 Discontinuation due to other reasons (n/N), 6 months ALN: 21/224 PLB: 11/230 |
| Curtis et al., 2012 | Retr. | USA | 1621/F (ZOL: 98.2; IBN1: 94.5; IBN2: 94.2)/NR | 10.2% (ZOL), 9.1% (IBN1), 7.7% (IBN2) | IBN1 and 2 (same drug – different cohorts); ZOL | 5 mg; 3 mg/IV/annually; quarterly | 62.5 (ZOL) 72.4 (IBN1) 46.1 (IBN2) | P (NR) | Number of infusions 18–27 months ZOL: 1.7 (SD = 0.5) IBN1: 4.4 (SD = 2.7) IBN2: 5.3 (SD = 2.9) 1 infusion recipients only (%) ZOL: 31.9 IBN1: 18.5 IBN2: 14 | PDC 18–27 months (mean, SD) ZOL: 82 (SD = 18), n = 775 IBN1: 58 (SD = 31), n = 275 IBN2: 62 (SD = 31), n = 571 PDC ≥ 80% at 18 months (%, ref.: ZOL) ZOL: 61 IBN1: 43, p < 0.0001 IBN2: 49, p < 0.0001 PDC ≥ 80% at 18–27 months (%) ZOL: 62.8, ref. IBN1: 36, p < 0.0001 IBN2: 33.3, p < 0.0001 |
| Curtis et al., 2006 | Retr. | USA | 1158/F: 77 (ALN); 80 (RIS)/ALN: 53 (13); RIS: 53 (13) | 13% (ALN) 10% (RIS) | ALN; RIS | 10 mg, 70 mg (ALN); 5 mg, 35 mg (RIS)/oral/daily, weekly | P (100) | NR | MPR (%, SD) ALN: 72 (26), n = 754 RIS: 74 (26), n = 404, p > 0.05 (NS) | Discontinuation (≥ 3 months gap, mean duration: 39 months), (HR, 95% CI) HR (ref.: RIS) = 1.04 (0.86 to 1.25) Computed by graph |
| Downey et al., 2006 | Retr. | USA | 9105/F (100)/64.4 (10.4) | NR | ALN; RIS | ALN: 10 mg, 70 mg (80.7%); RIS: 5 mg, 35 mg (69.2)/oral; weekly | NR | NR | MPR 12 months (% days on drug, SD) ALN: 60.7 (28.64), n = 6881, p < 0.001 RIS: 58.4 (28.64), n = 2224 | Discontinuation (mean time), 12 months ALN: 2.53, n = 6881 RIS: 2.53, n = 2224 Persistence rate (%) 12 months (refill gap ≥ 30 days) ALN: 1466/6881 (21.3%) RIS: 431/2224 (19.4%) |
| Duckworth et al., 2019 | RCT | UK | 421/F (86)/ALN: 63.8 (8.5); PLB: 63 (8.5) | P (100) | ALN; PLB | 70 mg/oral/weekly | NP | NR | Compliance (n/N), 6 months ALN: 184/215 PLB: 175/206 | Discontinuation (n/N, total), 6 months ALN: 17/215 PLB: 24/206 |
| Dugard et al., 2009 | Retr. | UK | 40/F (100)/74.5 (7.1) | P (48.4) | ALN; RIS | NR | P (10.2) | P (100) | MPR ≥ 80, 60 months ALN: 10/35 RIS: 2/5 | Persistence 5-year (n/N, refill gap ≥ 12 months) ALN: 18/35 RIS: 2/5 |
| Durden et al., 2017 | Retr. | USA | 33,435/F (100)/≈64.9 (10.4) | NR/ALN-daily: 9.4; ALN-weekly: 7.4; IBN-monthly: 5.7; IBN-quarterly: 5.5; RIS-daily: 11.3; RIS-weekly: 6.4; ZOL: 8.2 | ALN; IBN; RIS; ZOL | 10 mg, 70 mg; 3 mg; 150 mg; 5 mg, 35 mg; 5 mg/oral; IV/daily; weekly; quarterly; monthly; annual | NR | ALN-daily: 12.1; ALN-weekly: 16.8; IBN-monthly: 19; IBN-quarterly: 49.7; RIS-daily: 22.6; RIS-weekly: 24.3; ZOL: 49.2 | MPR ≥ 80% (%, n), 12 months: ALN-daily: 19.2 (n = 224) ALN-weekly: 31.3 (n = 19,486) IBN-monthly: 31.7 (n = 5981) IBN-quarterly: 20.6 (n = 165) RIS-daily: 26.4 (n = 53) RIS-weekly: 22.1 (n = 2968) ZOL: 98.5 (n = 4558) MPR ≥ 80% (%, n), 24 months: ALN-daily: 12.5 (n = 224) ALN-weekly: 22.8 (n = 19,486) IBN-monthly: 22.3 (n = 5981) IBN-quarterly: 15.2 (n = 165) RIS-daily: 11.3 (n = 53) RIS-weekly: 15.5 (n = 2968) ZOL: 38.5 (n = 4558) | Persistence 12-month, n/N (&), 60-day refill gap ALN-daily: 71/224 (31.7%) ALN-weekly: 7541/19,486 (38.7%) IBN-monthly: 2345/5981 (39.2%) IBN-quarterly: 56/165 (33.9%) RIS-daily: 23/53 (43.4%) RIS-weekly: 1000/2968 (33.7%) ZOL: 4558/4558 (100%) Persistence 24 months, n/N (&), 60-day refill gap ALN-daily: 44/224 (19.6%) ALN-weekly: 4618/19,486 (23.7%) IBN-monthly: 1370/5981 (22.9%) IBN-quarterly: 32/165 (19.4%) RIS-daily: 11/53 (20.8%) RIS-weekly: 606/2968 (20.4%) ZOL: 1545/4558 (33.9%) |
| Dursun et al., 2001 | RCT | Turkey | 101/F (100)/ALN: 60.26 (8.58); Calcium: 60.26 (8.58) | NR | ALN; PLB (calcium) | 10 mg/oral/daily | NR | P (100) | NR | Discontinuation (n/N, total), 24 months ALN: 13/51 PLB: 15/50 |
| Eastell et al., 2014 Extension Eastell et al., 2011 | RCT | European countries | 114/F (100)/ALN ≈ 65.7 (4.39); PLB ≈ 65 (4.9) | NR | ALN; PLB | 70 mg/oral/weekly | NR | P (ALN ≈ 82.5; PLB ≈ 82.5) | NR | Discontinuation (n/N, total), 12 months ALN: 5/57 PLB: 8/57 Discontinuation due to AEs (n/N), 12 months ALN: 3/57 PLB: 2/57 Discontinuation due to other reasons (n/N), 12 months ALN: 2/57 PLB: 6/57 Discontinuation (n/N, total), 24 months ALN: 3/41 PLB: 6/39 |
| Eisenberg et al., 2015 | Retr. | USA | 27,905/F (100)/66.1 (9.7) | NR | ALN; IBN; RIS | NR/oral/NR | NR | P (100) | MPR ≥ 70% 12 months (n/N, %), 13–24 months: ALN: 6725/15,917, 59.2, p < 0.001 IBN: 1974/5249, 17.4 RIS: 2669/6739, 23.5 Compliance (OR, SE) ALN: ref. IBN: 1.02 (1.07), p = 0.81 RIS: 0.92 (1.06), p = 0.14 Higher OR indicate higher likelihood to be compliant | Discontinuation 12 months (n/N, refill gap ≥ 60 days) ALN: 9585/15,917 IBN: 3441/5249 RIS: 4217/6739 |
| Eisman et al., 2004 | RCT | Multicentre (Europe; Americas; Africa; Asia-Pacific) | 449/F (94.2)/ALN: 63.6 (9); PLB: 63.6 (8.5) | NR | ALN; PLB | 70 mg/oral/weekly | NR | NR | NR | Discontinuation (n/N, total), 3 months ALN: 18/225 PLB: 10/224 Discontinuation due to AEs (n/N), 3 months ALN: 11/225 PLB: 6/224 Discontinuation due to other reasons (n/N), 3 months ALN: 7/225 PLB: 4/224 |
| Fan et al., 2013 | Retr. | USA | 44,635/F (100)/NR | NR | ALN; IBN; RIS | 70 mg; 35 mg; 150 mg/oral/weekly; monthly | NR | NR | MPR (%) ALN: 55, p < 0.05 IBN: 51 RIS: 52 | Persistence (45-day refill gap) (n/N, %) ALN: 8837/25,207, 35.1, p < 0.001 IBN: 225/739, 30.4, p < 0.001 RIS: 6066/18,689, 32.5, p < 0.001 Discontinuation (n/N, %, refill gap ≥ 45-day) ALN: 16,132/25,207, 64, p < 0.001 IBN: 504/739, 68.2, p < 0.001 RIS: 12,418/18,689, 66.4, p < 0.001 Discontinuation (HR, 95% CI) ALN: ref. IBN: 1.3(1.2 to 1.4), p < 0.001 RIS: 1.1 (1.06 to 1.11), p < 0.001 |
| Flodin et al., 2014 | RCT | Sweden | 53/F (70.8)/79 (9) | P (100) | RIS; PLB | 35 mg/oral/weekly | NR | NR | NR | Discontinuation (n/N, total), 12 months RIS: 3/28 PLB: 1/25 Discontinuation due to other reasons (n/N), 12 months RIS: 3/28 PLB: 1/25 |
| Fogelman et al., 2000 | RCT | Multicentre (France; UK; the Netherlands; Belgium; Germany) | 359/F (100)/RIS: 65 (6.7); PLB: 64 (6.7) | RIS: 32; PLB: 30 | RIS; PLB | 5 mg/oral/daily | NR | P (100) | NR | Discontinuation (n/N, total), 24 months RIS: 38/177 PLB: 37/180 Discontinuation due to AEs (n/N, total), 24 months RIS: 19/177 PLB: 14/180 Discontinuation due to other reasons (n/N, total), 24 months RIS: 19/177 PLB: 23/180 |
| Gallagher et al., 2008 | Retr. | UK | 44,531/F (81.2)/NR | 11,460 (25.7%) | ALN; RIS | 10 mg, 70 mg; 5 mg, 35 mg/oral/daily, weekly | P (32) | NR | MPR mean FUp ~ 2.3 years, OR (95% CI) ALN: ref. RIS: 1.30 (95% CI 1.22 to 1.39, more likely to be compliant), p < 0.05 | Persistence mean FUp ~ 2.3 years, RR (95% CI), (refill gap ≤ 3 months) ALN: ref. RIS: 1.06 (95% CI 1.02 to 1.09, more likely to continue), p < 0.05 |
| Gold et al., 2006 Ext.: Gold et al., 2009 | Retr. | USA | 6 months period: 208,762 (compliance); 240,001 (persistence); 12 months period: 232,489 (compliance); 263,383 (persistence)/F (IBN: 94.2; RIS: 93.2)/67.3 (9.4) | NR | IBN; RIS | 150 mg; 35 mg/oral/monthly; weekly | NR | P (100) | MPR (%, SD), 6 months IBN: 78.5 (20.4), p < 0.0001 RIS: 83.3 (17) MPR (%, SD), 12 months IBN: 74.68 (22.56), p < 0.0001 RIS: 80.15 (18.9) Mean CDA (%, SD%), 6 months IBN: 52.8 (31.5) RIS: 72.7 (24.6), p < 0.0001 Mean CDA (%, SD%), 12 months IBN: 43.38 (32.96) RIS: 64.54 (29.86), p < 0.0001 | Persistence (days, SD), 6 months (refill gap ≥ 90 days) IBN: 100.1 (67.4), p < 0.0001 RIS: 144.3 (55.5) Persistence (days, SD), 12 months (refill gap ≥ 90 days), HR (95% CI) IBN: 151.54 (137.24) RIS: 250.04 (132.34) HR = 1.77 (1.73 to 1.82), p < 0.0001 |
| Greenspan, Perrera et al., 2015 | RCT | USA | 181/F (100)/ZOL: 85.4 (5.66); PLB: 85.5 (4.8) | P (ZOL: 52; PLB: 41) | ZOL; PLB | 5 mg/IV/annually | P (NR) | P (ZOL: 48; PLB: 45) | NR | Discontinuation (n/N, total), 24 months ZOL: 25/89 PLB: 18/92 |
| Greenspan, Vujevich et al., 2015 | RCT | USA | 109/F (100)/RIS: 65 (1); PLB: 64 (1) | NP | RIS; PLB | 35 mg/oral/weekly | NP | NP | Compliance ≥ 80% (%), (range) RIS: 90–98 PLB: 89–96 | Discontinuation (n/N, total), 24 months RIS: 7/55 PLB: 7/54 |
| Greenspan et al., 2003 | RCT | USA | 186/F (100)/ALN: 71 (4); PLB: 72 (5) | P (ALN: 39; PLB: 33) | ALN; PLB | 10 mg/oral/daily | NP | NR | Compliance ≥ 80% medication ALN: 58/93 PLB: 63/93 | Discontinuation (n/N, total), 36 months ALN: 8/93 PLB: 10/93 |
| Grey et al., 2017 Ext. Grey et al., 2014 Grey et al., 2012 | RCT | New Zealand | 90/F (100)/ZOL: 66 (8); PLB: 63 (8) | NP | ZOL; PLB | 5 mg/IV/annually | NP | NP | NR | Discontinuation (n/N), 12 months ZOL: 3/45 PLB: 3/45 Discontinuation (n/N), 24 months ZOL: 3/45 PLB: 6/45 Discontinuation (n/N), 60 months ZOL: 5/41 PLB: 9/34 |
| Hadji et al., 2016 | Retr. | Germany | 138,839 (ALN: 90,077; IBN-oral: 6235; IBN-IV: 20,472; RIS: 18,089; ZOL: 3966)/F (100)/NR | NR | ALN; IBN-oral; IBN-IV; RIS; ZOL | 70 mg; 150 mg; 3 mg; 35 mg; 5 mg/oral; IV/weekly; monthly; annually | NR | NR | NR | Persistence in % (≥60-day refill gap), 12 months ALN: 30.1 IBN-oral: 30.1 IBN-IV: 42.9 RIS: 31.4 ZOL: 33.8 Persistence in % (≥60-day refill gap), 24 months ALN: 17.3 IBN-oral: 16.7 IBN-IV: 24.8 RIS: 17.5 ZOL: 20.9 |
| Persistence in % (≥ 30-day refill gap), 12 months ALN: 21.5 IBN-oral: 18.4 IBN-IV: 31.1 RIS: 22.6 ZOL: 20.3 Persistence in % (≥ 30-day refill gap), 24 months ALN: 9.7 IBN-oral: 7.3 IBN-IV: 15 RIS: 10.2 ZOL: 6.5 | ||||||||||
| Persistence in % (≥ 90-day refill gap), 12 months ALN: 35.6 IBN-oral: 35 IBN-IV: 48.2 RIS: 36.9 ZOL: 39.7 Persistence in % (≥ 90-day refill gap), 24 months ALN: 22.5 IBN-oral: 21.2 IBN-IV: 30.2 RIS: 22.6 ZOL: 29.5 | ||||||||||
| Persistence in % (≥ 120-day refill gap), 12 months ALN: 39.7 IBN-oral: 39.4 IBN-IV: 54.4 RIS: 41.4 ZOL: 43.7 Persistence in % (≥120-day refill gap), 24 months ALN: 26.5 IBN-oral: 25.1 IBN-IV: 36.7 RIS: 26.9 ZOL: 34.1 | ||||||||||
| Hadji et al., 2014 | Prosp. | Germany | 1802/F (100)/ ALN: 71.7 (9.3); IBN: 71.8 (9.3) | P (NR) | ALN; IBN | 70 mg; 3 mg/oral; IV/weekly; quarterly | P (NR) | P (100) | Discontinuation due to non-compliance (n, %) IBN: 130/901 (14.4%) ALN: 229/901 (25.4%), p < 0.001 | Persistence (days) 12 months IBN: 343, n = 901 ALN: 327, n = 901, p < 0.001 |
| Hadji et al., 2012 | RCT | Germany | 604/F (100)/ALN: 68.1 (7.86); ZOL: 67.6 (8.05) | NP | ALN; ZOL | 70 mg; 5 mg/oral; IV/weekly; annually | NP | P (100) | Compliance rate (%) ALN: 80.9 ZOL: NR | Discontinuation (n/N, total), 12 months ALN: 24/196 ZOL: 19/408 |
| Halpern et al., 2011 | Retr. | USA | 17,284 (ALN: 10,068; IBN: 651; RIS: 6565)/F (100)/commercial: 59.3 (8.6); medicare: 75.7 (6.5) | Commercial: 4; medicare: 6.8 | ALN; IBN; RIS | 5 mg, 10 mg; NR; 5 mg, 35 mg/oral/daily, weekly | Commercial: 17.9; medicare: 16.5 | P (100) | MPR ≤ 50%(%) (commercial) (FUp: 180 days) ALN: 32 IBN: 30 RIS: 31.4 MPR ≤ 50%(%) (medicare) (FUp: 180 days) ALN: 42.7 IBN: 28.5 RIS: 44 | NR |
| Hansen et al., 2013; Hansen et al., 2015 | Retr. | Denmark | 100,556 (total population)/F (84.5)/70.4 | P (39) | ALN; IBN; RIS | NR | P (24) | NR | NR | Persistence in mean years (mean FUp ~ 5.2 years, 56-day refill gap) ALN: 4.01 (95% CI = 3.96 to 4.06) IBN: 3.86 (95% CI = 3.5 to 4.22) RIS: 2.79 (95% CI = 2.69 to 2.89) Discontinuation 60 months (n/N, %) ALN: 3504/15,235, 23 IBN: 321/1459, 22 RIS: 91/276, 33 |
| Ho and Kung, 2005 | RCT | Hong Kong | 58/F (100)/ALN: 60.6 (5.5); PLB: 62 (4) | P (37) | ALN; PLB (Calcium) | 70 mg/oral/weekly | NR | P (100) | NR | Discontinuation (n/N, total), 12 months ALN: 1/29 PLB: 3/29 |
| Hooper et al., 2005 | RCT | Australia | 254/F (100)/RIS: 52.5 (3.1); PLB: 52.6 (3.3) | P (19.5) | RIS; PLB | 5 mg/oral/daily | NR | NP | NR | Discontinuation (n/N, total), 24 months RIS: 26/129 PLB: 32/125 Discontinuation due to AEs (n/N, total), 24 months RIS: 7/129 PLB: 8/125 Discontinuation due to other reasons (n/N, total), 24 months RIS: 19/129 PLB: 24/125 |
| Iolascon et al., 2013 | Retr. | Italy | 12,798/F (92.2)/ALN: 68.6 (10.2); ALN + Vit. D: 69 (10.1); IBN: 68.6 (9.9); RIS: 68.4 (10.2) | NR | ALN; ALN + Vit. D; IBN; RIS | NR/oral/NR | NR | NR | NR | Persistence 12 months (n/N, %) (30-day refill gap) ALN: 292/2317, 12.6 ALN + Vit. D: 707/4501, 15.7 IBN: 341/1581, 21.6 RIS: 695/4399, 15.8 |
| Jones et al., 2008 | Retr. | Canada | 37,032/F (100)/NR | NR | ALN; RIS | 70 mg; 35 mg/oral/weekly | NR | NR | NR | Persistence (n/N, %) 6 months (30-day refill gap) ALN: 16,752/23,266, 72, p = 0.11 RIS: 9801/13,766, 71.2 Persistence 12 months (n/N, %) (30-day refill gap) ALN: 13,099/23,266, 56.3, p < 0.0001 RIS: 7489/13,766, 54.4 |
| Karimi et al., 2019 | RCT | Iran | 80/F (100)/ALN: 56.5 (6.3); PLB: 55.3 (4.0) | NR | ALN; PLB | 70 mg/oral/weekly | NP | NR | P (100) | Discontinuation (n/N, total), 3 months ALN: 10/40 PLB: 10/40 |
| Kjellberg et al., 2016 | Retr. | Denmark | 38,234/F (100)/71.7 (9.24) | NR/21.2 | ALN; IBN; RIS | NR/oral/NR | NR | P (33.6) | MPR ≥ 70%, OR (95% CI) (higher ORs indicate higher compliance) ALN: ref. IBN: 1.49 (1.32 to 1.68), p < 0.001 RIS: 0.84 (0.74 to 0.96), p = 0.011 | NR |
| Klotz et al., 2013 | RCT | Canada | 186/F (0)/ALN ≈ 73.5 (8.1); PLB ≈ 73.7 (8.6) | P (43) | ALN; PLB | 70 mg/oral/weekly | NP | NA | NR | Discontinuation (n/N, total), 12 months ALN: 6/84 PLB: 10/102 Discontinuation due to AEs (n/N, total), 12 months ALN: 0/84 PLB: 6/102 Discontinuation due to other reasons (n/N, total), 12 months ALN: 6/84 PLB: 4/102 |
| LaFleur et al., 2015 | Retr. | USA | 35,650/F (100)/65.7 (12.5) | P (21.1) | ALN; IBN; RIS; ZOL | NR/oral; IV/NR | P (11.9) | P (19.7) | NR | Discontinuation (n/N), HR (95% CI), mean FUp ~ 52.8 months (90-day refill gap) ALN: 26,571/32,971, HR = ref. IBN: 52/78, HR = 0.86 (0.67 to 1.14), p > 0.05(NS) RIS: 1845/2261, HR = 1.07 (1.02 to 1.12), p < 0.05 ZOL: 155/340, HR = 0.58 (0.49 to 0.68), p < 0.05 |
| Landfeldt et al., 2012 | Retr. | Sweden | 54,883/F (ALN: 85.8); (RIS: 87.4)/ALN: 71.1 (10); RIS: 69.7 (10) | P (ALN: 15.4); P (RIS: 15.1) | ALN; RIS | 70 mg; 35 mg/oral/weekly (> 95% in both arms) | P (ALN: 19.6); (RIS: 19.9) | NR | NR | Persistence proportion (%, 95% CI n/N) maximum FUp: 2.33 years (refill gap ≥ 8 weeks) ALN: 51.7 (51.2 to 52.2), 23,920/46,265 RIS: 50.6 (49.5 to 51.8), 4361/8618 |
| Lewiecki et al., 2008 | Prosp. | USA | 545/F (100)/66 (10.6) | P (32) | IBN-oral/IBN-IV | 150 mg; 3 mg/oral; IV/monthly; quarterly | P (9.8) | P (68.13) | Drug-intake ≥ 75% IBN-IV: 325/392 IBN-oral: 101/145 | Discontinuation 12 months (n/N) IBN-IV: 86/396 IBN-oral: 40/149 Discontinuation due to AEs 12 months (n/N) IBN-IV: 41/396 IBN-oral: 25/149 Discontinuation due to other reasons 12 months (n/N) IBN-IV: 45/396 IBN-oral: 15/149 |
| Lester et al., 2008 | RCT | UK | 50/F (100)/IBN: 66.7 (11.39); PLB: 67.36 (5.81) | NR | IBN; PLB | 150 mg/oral/monthly | NR | NR | NR | Discontinuation (n/N, total), 24 months IBN: 4/25 PLB: 6/25 Discontinuation due to AEs (n/N, total), 24 months IBN: 2/25 PLB: 1/25 Discontinuation due to other reasons (n/N, total), 24 months IBN: 2/25 PLB: 5/25 |
| Li et al., 2012 | Retr. | UK | 44,526/F (100)/71.4 (11) | P (32.3) | ALN; IBN; RIS | 5 mg, 10 mg; 70 mg; 30 mg, 35 mg; 150 mg/oral/daily; weekly; monthly | P (20.6) | P (58.1) | NR | Persistence (median time in days, 95% CI) ALN (daily): 56, NR RIS (daily): 98 (86 to 110) ALN (weekly): 221 (211 to 224) RIS (weekly): 223 (210 to 225) IBN (monthly): 300 (270 to 338) Rates of persistence 6 months (%, 95% CI), (n/N), (≥ 30 days refill gap) ALN (daily): 27.0 (26.3 to 27.7), 1379/5107 RIS (daily): 37.8 (36.5 to 39.1), 725/1918 ALN (weekly): 52.8 (52.4 to 53.1), 14,899/28,218 RIS (weekly): 53.1 (52.4 to 53.7), 4598/8660 |
| IBN (monthly): 56.8 (55.1 to 58.5), 354/623 Rates of persistence 12 months (%, 95% CI), (n/N), (≥ 30 days refill gap) ALN (daily): 17.6 (16.9 to 18.2), 899/5107 RIS (daily): 26.4 (25.2 to 27.6), 506/1918 ALN (weekly): 41.3 (40.9 to 41.7), 11,654/28,218 RIS (weekly): 41.0 (40.3 to 41.6), 3551/8660 IBN (monthly): 46.5 (44.7 to 48.3), 290/623 Rates of persistence 36 months (%, 95% CI), (n/N), (≥ 30 days refill gap) ALN (daily): 6.5 (6.0 to 6.9), 332/5107 RIS (daily): 9.6 (8.8 to 10.5), 184/1918 ALN (weekly): 24.6 (24.2 to 25.0), 6942/28,218 RIS (weekly): 19.5 (18.9 to 20.1), 1689/8660 IBN (monthly): 32.1 (29.8 to 34.3), 200/623 Rates of persistence 60 months (%, 95% CI), (n, N), (≥ 30 days refill gap) | ||||||||||
| ALN (daily): 2.8 (2.5 to 3.1), 143/5107 RIS (daily): 4.9 (4.3 to 5.6), 94/1918 ALN (weekly): 16.9 (16.5 to 17.3), 4769/28,218 RIS (weekly): 8.9 (8.2 to 9.6), 771/8660 IBN (monthly): NA | ||||||||||
| Liang et al., 2017 | RCT | China | 285/F (100)/ZOL: 57.22 (2.81); PLB: 57.48 (3.18) | P (NR) | ZOL; PLB | 5 mg/IV/annually | NR | P (100) | NR | Discontinuation (n/N), 6 months ZOL: 5/175 PLB: 5/110 Discontinuation (n/N), 12 months ZOL: 10/175 PLB: 10/110 Discontinuation (n/N), 24 months ZOL: 20/175 PLB: 15/110 |
| Lima et al., 2019 | Prosp. | Brazil | 158/F (61.66)/RIS: 55.6 (39.54); PLB: 52.66 (32.62) | NR | RIS; PLB | 35 mg/oral/weekly | NP | P (28) | NR | Discontinuation (n/N), 12 months RIS: 8/73 PLB: 7/85 |
| Liu et al., 2019 | RCT | China | 482/F (ZOL: 47.87, PLB: NR) | P (ZOL: 9.91; PLB: 12.4) | ZOL; PLB | 5 mg/IV/annually | NP | NP | NR | Discontinuation (n/N, total), 12 months ZOL: 6/353 PLB: 3/129 Discontinuation (n/N, total), 24 months ZOL: 14/353 PLB: 8/129 |
| Livi et al., 2019 | RCT | Italy | 171/F (100)/IBN: 60.6 (9.57); PLB: 60.5 (10.64) | NP | IBN; PLB | 150 mg/oral/monthly | NR | NP | NR | Discontinuation (n/N, total), 60 months IBN: 17/89 PLB: 10/82 Discontinuation due to AEs (n/N, total), 60 months IBN: 5/89 PLB: 1/82 Discontinuation due to other reasons (n/N, total), 60 months IBN: 12/89 PLB: 9/82 |
| Lyles et al., 2007 | RCT | International | 2127/F (ZOL: 76.7; PLB: 75.5)/ZOL: 74.4 (9.48); PLB: 74.6 (9.86) | P (NR) | ZOL; PLB | 5 mg/IV/annually | NR | P (ZOL: 42.3; PLB: 41.1) | NR | Discontinuation (n/N, total), 36 months ZOL: 295/1065 PLB: 316/1062 Discontinuation due to AEs (n/N, total), 36 months ZOL: 21/1065 PLB: 18/1062 Discontinuation due to other reasons (n/N, total), 36 months ZOL: 274/1065 PLB: 298/1062 |
| McClung et al., 2014 | RCT | Argentina, Austria, Belgium, Canada, Denmark, Spain and USA | 103/F (100)/ALN: 67.1 (5.8); PLB: 67 (6.5) | NP | ALN; PLB | 70 mg/oral/weekly | NP | P (100) | NR | Discontinuation (n/N, total), 12 months ALN: 2/51 PLB: 5/52 Discontinuation due to AEs (n/N, total), 12 months ALN: 0/51 PLB: 1/52 Discontinuation due to other reasons (n/N, total), 12 months ALN: 2/51 PLB: 4/52 |
| McClung, Bolognese et al., 2009 | RCT | USA | 160/F (100)/IBN: 53.7 (3.6); PLB: 53.4 (3.8) | NP | IBN; PLB | 150 mg/oral/monthly | NR | NP | NR | Discontinuation (n/N, total), 12 months IBN: 12/77 PLB: 10/83 |
| McClung, Miller et al., 2009 | RCT | USA | 383/F (100)/ZOL: 59.6 (8.0); PLB: 60.5 (8.0) | NP | ZOL; PLB | 5 mg/oral/annually | NR | NP | NR | Discontinuation (n/N, total), 24 months ZOL: 27/181 PLB: 14/202 Discontinuation due to AEs (n/N, total), 24 months ZOL: 3/181 PLB: 1/202 Discontinuation due to other reasons (n/N, total), 24 months ZOL: 24/181 PLB: 13/202 |
| McClung et al., 2007 | RCT | USA | 225/F (100)/ZOL: 67.6 (8.3); ALN: 68.0 (7.5) | NR | ZOL; ALN | 5 mg; 70 mg/IV; oral/annually; weekly | NR | P (ZOL: 41.6; ALN: 30.4) | NR | Discontinuation (n/N, total), 24 months ZOL: 7/113 ALN: 2/112 Discontinuation due to AEs (n/N, total), 24 months ZOL: 4/113 ALN: 1/112 Discontinuation due to other reasons (n/N, total), 24 months ZOL: 3/113 ALN: 1/112 |
| Miller et al., 2008 | RCT | North and Latin America; Europe; South Africa | 1747/F (100)/ALN: 65.6; IBN: 65.6 | P (ALN: 38.2; IBN: 39) | ALN; IBN | 70 mg; 150 mg/oral/weekly; monthly | NR | P (100) | NR | Discontinuation (n/N), 12 months ALN: 88/873 IBN: 86/874 |
| Modi et al., 2017 | Retr. | USA | 3,361/F (100)/IBN: 71.5 (7.6); ZOL: 72.6 (7.3) | P (IBN: 9.4; ZOL: 12.2) | IBN; ZOL | 3 mg; 5 mg/IV/quarterly; annually | P (IBN: 30; ZOL: 26.4) | P (IBN: 87.1; ZOL: 87.3) | NR | Discontinuation (%), 6 months IBN (30-day refill gap): 60.5, n = 233 ZOL (30-day refill gap): NA, n = 3128 IBN (60-day refill gap): 54.5 ZOL (60-day refill gap): NA IBN (90-day refill gap): 49.4 ZOL (90-day refill gap): NA Discontinuation (%), 12 months IBN (30-day refill gap): 77.7 ZOL (30-day refill gap): 73.5 |
| IBN (60-day refill gap): 72.1 ZOL (60-day refill gap): 64.5 IBN (90-day refill gap): 69.1 ZOL (90-day refill gap): 59.2 Discontinuation (%), 18 months IBN (30-day refill gap): 87.7 ZOL (30-day refill gap): NA IBN (60-day refill gap): 83.1 ZOL (60-day refill gap): NA IBN (90-day refill gap): 80.9 | ||||||||||
| ZOL (90-day refill gap): NA Discontinuation (%), 24 months IBN (30-day refill gap): 91.5 ZOL (30-day refill gap): 89.1 IBN (60-day refill gap): 88.1 ZOL (60-day refill gap): 82.8 IBN (90-day refill gap): 87.5 ZOL (90-day refill gap): 79.8 | ||||||||||
| Nakamura et al., 2017 | RCT | Japan | 665/F (ZOL: 93.63; PLB: 94.25)/ZOL: 74 (5.4); PLB: 74.3 (5.4) | P (ZOL: 91.2; PLB: 89.4) | ZOL; PLB | 5 mg/oral/annually | NR | P (ZOL: 62.4; PLB: 72) | NR | Discontinuation (n/N, total), 24 months ZOL: 75/333 PLB: 48/332 Discontinuation due to AEs (n/N, total), 24 months ZOL: 15/333 PLB: 6/332 Discontinuation due to other reasons (n/N, total), 24 months ZOL: 60/333 PLB: 42/332 |
| Netelenbos et al., 2011 | Retr. | The Netherlands | 7994 (persistence); 100,684 (compliance)/F (80)/NR | NR | ALN; IBN; RIS | 10 mg, 70 mg; 150 mg; 5 mg, 35 mg/oral/daily weekly; monthly; daily, weekly | P (31.1) | P (14.2) | MPR ≥ 80% (%, n), 12-month ALN (daily): 92.2, n = 3101 ALN (weekly): 91.2, n = 55,195 ALN (weekly) plus vitamin D3: 92.3, n = 8279 IBN: 89, n = 3279 RIS (daily): 91.6, n = 1010 RIS (weekly): 91.5, n = 24,866 RIS (weekly) plus calcium: 93.1, n = 4954 | Persistence 12-month (n/N, &) (refill gap ≤ 12 months) ALN (daily): 60/241 (23.2%) ALN (weekly): 1605/3698 (43.4%) ALN (weekly) plus vitamin D3: 509/965 (52.7%) IBN: 205/443 (46.3%) RIS (daily): 33/82 (40.2%) RIS (weekly): 825/1818 (45.4%) RIS (weekly) plus calcium: 317/747 (42.4%) |
| Orwoll, Binkley et al., 2010 | RCT | USA | 135/F (0)/IBN: 63.9 (11.2); PLB: 65 (10.6) | P (IBN: 48; PLB: 32) | IBN; PLB | 150 mg/oral/monthly | NP | P (NR) | Compliance (≥ 80%), (n/N), 12 months IBN: 69/85 PLB: 40/47 | Discontinuation (n/N, total), 12 months IBN: 16/87 PLB: 6/48 Discontinuation due to AEs (n/N, total), 12 months IBN: 4/87 PLB: 3/48 Discontinuation due to other reasons (n/N, total), 12 months IBN: 12/87 PLB: 3/48 |
| Orwoll, Miller, et al., 2010 | RCT | North America; Australia | 302/F (0)/64.0 (10.44) | P (ZOL: 63.6; ALN: 70.3) | ZOL; ALN | 5 mg; 70 mg/IV; oral/annually; weekly | NP | P (ZOL: 42.4; ALN: 35) | Compliance (≥ 80%), (n/N), 24 months ZOL: 128/154 ALN: 120/148 | Discontinuation (n/N, total), 24 months ZOL: 17/154 ALN: 24/148 Discontinuation due to AEs (n/N, total), 24 months ZOL: 6/154 ALN: 12/148 Discontinuation due to other reasons (n/N, total), 24 months ZOL: 11/154 ALN: 12/148 |
| Orwoll et al., 2000 | RCT | USA and 10 other countries | 241/F (0)/ALN: 63 (13); PLB: 63/12 | P (ALN: 49; PLB: 52) | ALN; PLB | 10 mg/oral/daily | NR | P (NR) | NR | Discontinuation (n/N, total), 24 months ALN: 21/146 PLB: 16/95 |
| Overbeek et al., 2017 | Retr. | The Netherlands | 35,557/F (74–99)/NR | NR | ALN; IBN; RIS; ZOL | 10 mg, 70 mg; 150 mg; 5 mg, 35 mg; 5 mg/oral; IV/daily; weekly; monthly; annually | NR | NR | NR | Persistence (refill gap ≤ 60 days), 12 months ALN (daily): 140/661 ALN (weekly): 12,417/22,165 IBN-IV: 28/40 IBN-oral: 907/1742 RIS (daily): 69/230 RIS (weekly): 5815/10,483 ZOL: 236/236 Persistence (refill gap ≤ 60 days), 24 months ALN (daily): 78/532 |
| ALN (weekly): 7658/17,645 IBN-IV: 13/29 IBN-oral: 619/1575 RIS (daily): 32/205 RIS (weekly): 3699/8943 ZOL: 106/162 | ||||||||||
| Paggiosi et al., 2014 | RCT | UK | 172/F (100)/IBN: 66.9 (7.2); ALN: 67.8 (7.8); RIS: 66.8 (6.7) | P (IBN: 9; ALN: 23; RIS: 7) | IBN; ALN; RIS | 150 mg; 70 mg; 35 mg/oral/monthly; weekly; weekly | NR | P (NR) | Compliance in % (table count) IBN: 85.8 ALN: 80.9 RIS: 71.6 | Discontinuation (n/N, total), 12 months IBN: 14/57 ALN: 13/57 RIS: 12/58 Discontinuation (n/N, total), 24 months IBN: 25/57 ALN: 26/57 RIS: 27/58 |
| Pazianas et al., 2012 | Retr. | USA | 264,679/F (92.4)/64.9–65.8 | P (≈ 9.65) | ALN; RIS | NR/oral/NR | P (17.7) | NR | MPR ≥ 66.6%, 36 months FUp ALN: 63,273/167,366 RIS: 38,081/97,313 OR (95% CI) = 0.945 (0.93 to 0.96), p < 0.001 (favouring RIS group) | NR |
| Penning-van Beest et al., 2006 | Retr. | The Netherlands | 1446/F (100)/71.6 (8.7) | P (2.2) | ALN; RIS | 10 mg, 70 mg; 5 mg/oral/daily; weekly; daily | P (23.49) | NR | NR | Persistence 12-month (≤30 days refill gap), RR (95% CI) (higher RR more likely to persist) ALN (daily): 327/946, Ref. ALN (weekly): 176/339, RR = 1.56 (1.32 to 1.85) RIS (daily): 68/161, RR = 1.15(0.92 to 1.43) |
| Reid et al., 2018 | RCT | New Zealand | 2000/F (100)/ZOL: 71 (5); PLB: 71 (5.1) | P (ZOL: 23.7; PLB: 23.8) | ZOL; PLB | 5 mg/IV/annually | NR | NP | NR | Discontinuation (n/N, total), 72 months ZOL: 64/1000 PLB: 75/1000 |
| Reid et al., 2009 | RCT | European countries (12); Australia; Hong Kong; Israel; USA | 833/RIS: 67; ZOL: 68/54.56 (14.26); ZOL: 54.27 (14.55) | P (14) | RIS; ZOL | 5 mg; 5 mg/oral; IV/daily; annually | P (100) | P (NR) | NR | Discontinuation (n/N, total), 12 months ZOL: 31/416 RIS: 31/417 Discontinuation due to AEs (n/N, total), 12 months ZOL: 9/416 RIS: 6/417 Discontinuation due to other reasons (n/N, total), 12 months ZOL: 22/416 RIS: 25/417 |
| Reid et al., 2006 Extension of Reid et al., 2008 | RCT | Europe; Middle East; Americas; Asia-Pacific | 936/F (100)/ALN: 64.3; RIS: 63.6 | P (ALN: 35.5; RIS: 31.8) | ALN; RIS | 70 mg; 35 mg/oral/weekly | NR | P (NR) | NR | Discontinuation (n/N, total), 12 months ALN: 38/468 RIS: 44/468 Discontinuation due to AEs (n/N, total), 12 months ALN: 19/468 RIS: 29/468 Discontinuation due to other reasons (n/N, total), 12 months ALN: 19/468 RIS: 15/468 Discontinuation (n/N, total), 24 months ALN: 366/403 RIS: 350/395 |
| Reid et al., 2000 | RCT | Europe | 196/F (PLB: 62; RIS: 64)/PLB: 59 (12); RIS: 58 (12) | P (PLB: 37; RIS: 35) | RIS; PLB | 5 mg/oral/daily | P (100) | P (PLB: 33; RIS: 34) | NR | Discontinuation (n/N, total), 12 months RIS: 18/100 PLB: 24/96 Discontinuation due to AEs (n/N, total), 12 months RIS: 16/100 PLB: 17/96 Discontinuation due to other reasons (n/N, total), 12 months RIS: 2/100 PLB: 7/96 |
| Reyes et al., 2017 | Retr. | Spain | 13,035/F (100)/NR | P (23.89) | ALN; IBN; RIS | NR | NR | P (60.37) | NR | Persistence (≤ 90-day refill gap), 12 months ALN: 5223/10,938 IBN: 450/1115 RIS: 328/982 Persistence (≤ 90-day refill gap), 24 months ALN: 3159/10,938 IBN: 214/1115 RIS: 169/982 12-month IR of discontinuation (95% CI) ALN: 74.17 (72.27 to 76.12) IBN: 90.11 (83.51 to 97.22) |
| RIS: 111.25 (103.05 to 120.12) 24-month IR of discontinuation (95% CI) ALN: 66.3 (64.84 to 67.79) IBN: 86.02 (80.58 to 91.82) RIS: 98.62 (92.06 to 105.63) | ||||||||||
| Ringe et al., 2006 Extension of Ringe et al., 2009 | RCT | Germany | 316/F (0)/RIS: 55.8 (10.5); PLB: 58 (10.3) | P (RIS: 51.3; PLB: 51.3) | RIS; PLB | 5 mg/oral/daily | NR | P (RIS: 59.5; PLB: 58.2) | NR | Discontinuation (n/N, total), 24 months RIS: 10/158 PLB: 6/158 |
| Sambrook et al., 2012 | RCT | Australia; Belgium; Czechia; Estonia; Finland; France; Hong Kong; Hungary; Israel; Lithuania; Poland; Romania; Spain; Switzerland; UK; USA | 265/F (0)/56.4 (14.33) | NR | ZOL; RIS | 5 mg; 5 mg/IV; oral/annually; daily | P (100) | NR | NR | Discontinuation (n/N, total), 12 months ZOL: 14/131 RIS: 14/134 Discontinuation due to AEs (n/N, total), 12 months ZOL: 4/131 RIS: 2/134 Discontinuation due to other reasons (n/N, total), 12 months ZOL: 10/131 RIS: 12/134 |
| Scotti et al., 2014 | Retr. | Italy | 28,558/F (100)/72 (9.6) | NR | ALN; RIS | 10 mg, 70 mg; 5 mg; 35 mg/oral/daily; weekly | P (37.4) | P (100) | NR | PDC ≥ 80% (mean FUp ~ 5.3 years) ALN: 3153/23,454 RIS: 1022/5104 |
| Sestak et al., 2014 Extension Sestak et al., 2019 | RCT | International (Europe; Pacific Ocean) | 500/F (100)/60 | NP | RIS; PLB | 35 mg/oral/weekly | NR | NP | NR | Discontinuation (n/N, total), 36 months RIS: 108/253 PLB: 89/247 Discontinuation (n/N, total), 60 months RIS: 128/253 PLB: 114/247 |
| Sheehy et al., 2009 | Retr. | Canada | 32,804/F: 91.1 (RIS-br.), 89.2 (ALN-br.), 86.6 ALN (gen.)/NR | 3.8 (RIS-br.), 4.1 (ALN-br.), 7.2 ALN (gen.) | ALN; RIS | 70 mg; 35 mg/oral/weekly | NR | NR | NR | Discontinuation (refill gap ≥ 1.5 times the duration of dispensation) ALN (br.): ref. ALN (gen.): HR = 2.08 (1.89, 2.28) RIS (br.): HR = 1.11 (1.07, 1.15) |
| Shi et al., 2017 | RCT | China | 160/F (100)/ALN: 59.8 (4.7); PLB: 59.4 (4.5) | P (NR) | ALN; PLB | 70 mg/oral/weekly | NP | P (100) | NR | Discontinuation (n/N, total), 12 months ALN: 6/80 PLB: 9/80 Discontinuation due to AEs (n/N, total), 12 months ALN: 1/80 PLB: 0/80 Discontinuation due to other reasons (n/N, total), 12 months ALN: 5/80 PLB: 9/80 |
| Shilbayeh et al., 2004 | RCT | Jordan | 63/F (100)/57 | NR | ALN; PLB | 10 mg/oral/daily | NR | P (50) | NR | Discontinuation (n/N, total), 12 months ALN: 7/27 PLB: 18/36 |
| Shin et al., 2017 | RCT | South Korea | 167/F (100)/IBN: 54.5 (9.3); PLB: 55.1 (8.6) | NP | IBN; PLB | 150 mg/oral/monthly | P (100) | NP | NR | Discontinuation (n/N, total), 12 months IBN: 22/86 PLB: 18/81 Discontinuation due to AEs (n/N, total), 12 months IBN: 1/86 PLB: 0/81 Discontinuation due to other reasons (n/N, total), 12 months IBN: 21/86 PLB: 18/81 |
| Siris et al., 2011 | Retr. | USA | 460,584/F (100)/63.6 (10.9) | P (1.24–2.8) | ALN; IBN; RIS | NR/oral/NR | P (15.8 – 20) | P (32.4 – 36.2) | Mean MPR (%, n/N) (mean FUp: 2.4 years) ALN: 53.3 IBN: 56 RIS: 53.1 | NR |
| Smith et al., 2004 | RCT | Australia | 145/F (49)/67 (8.6) | P (NR) | ALN; PLB | 10 mg/oral/daily | P (Inhaled corticosteroids: 88; oral corticosteroids: 17) | P (100) | Compliance (median, IQR) ALN: 0.97 (0.09) PLB: 0.96 (0.095) | Discontinuation (n/N, total), 12 months ALN: 24/65 PLB: 26/79 |
| Reginster et al., 2000 Ext.: Sorensen et al., 2003 | RCT | Australia and Europe | 814/F (100)/RIS: 71 (7); PLB: 71 (7) | P (100) | RIS; PLB | 5 mg/oral/daily | NP | P (100) | NR | Discontinuation (n/N, total), 12 months RIS: 74/407 PLB: 77/407 Discontinuation (n/N, total), 36 months RIS: 156/407 PLB: 186/407 Discontinuation due to AEs (n/N, total), 36 months RIS: 65/407 PLB: 83/407 Discontinuation due to other reasons (n/N, total), 36 months |
| RIS: 91/407 PLB: 103/407 Discontinuation (n/N, total), 60 months RIS: 20/135 PLB: 25/130 Discontinuation due to AEs (n/N, total), 60 months RIS: 10/135 PLB: 16/130 Discontinuation due to other reasons (n/N, total), 60 months RIS: 10/135 PLB: 9/130 | ||||||||||
| Stoch et al., 2009 | RCT | USA | 173/F (ALN: 61.4; PLB: 52.5)/ALN: 51.9 (14.4); PLB: 54.6 (14.8) | NP | ALN; PLB | 70 mg/oral/weekly | P (100) | P (100) | Compliance (% actual n of days vs. expected n of days) ALN: 87.4 PLB: 88.5 | Discontinuation (n/N, total), 12 months ALN: 33/114 PLB: 16/59 Discontinuation due to AEs (n/N, total), 12 months ALN: 10/114 PLB: 11/59 Discontinuation due to other reasons (n/N, total), 12 months ALN: 23/114 PLB: 5/59 |
| Stuss et al., 2016 | RCT | Poland | 54/F (100)/IBN: 68. 1(8.1); PLB: 69.2 (8.1) | P (IBN: 28.6; PLB: 6.7) | IBN; PLB | 150 mg/oral/monthly | NP | P (100) | NR | Discontinuation (n/N, total), 6 months IBN: 5/34 PLB: 5/20 Discontinuation due to AEs (n/N, total), 6 months IBN: 3/34 PLB: 0/20 Discontinuation due to other reasons (n/N, total), 6 months IBN: 2/34 PLB: 5/20 |
| Valimaiki et al., 2007 | RCT | Finland; The Netherlands; Norway; Spain; Sweden | 171/F (100)/65.9 (6.8) | P (NR) | RIS; PLB | 5 mg/oral/daily | NP | NP | Compliance (mean, SD), 24 months RIS: 0.938 (0.141) PLB: 0.901 (0.164) Compliance mean (%, SD) RIS: 93.8 (14.14) PLB: 90.1 (16.46) | Discontinuation (n/N), 12 months RIS: 16/114 PLB: 14/57 Discontinuation (n/N, total), 24 months RIS: 19/114 PLB: 14/56 Discontinuation due to AEs (n/N, total), 24 months RIS: 10/114 PLB: 9/56 Discontinuation due to other reasons (n/N, total), 24 months RIS: 9/114 PLB: 5/56 Mean persistence in days (SD) RIS: 646.6 (207.9) PLB: 622.9 (230.8) |
| Van Bodegraven et al., 2014 | RCT | The Netherlands | 131/F (54)/42 (13) | NR | RIS; PLB | 35 mg/oral/weekly | NP | NP | NR | Discontinuation (n/N, total), 24 months RIS: 8/64 PLB: 5/67 |
| Van Boven et al., 2013 | Retr. | The Netherlands | 8445/F (75.6)/67.5 (13.5) | NR | ALN; RIS; IBN | 10 mg, 70 mg (ALN); 5 mg, 35 mg (RIS); 150 mg (IBN)/oral/daily and weekly (ALN; RIS); monthly (IBN) | P (21.2) | P (NR) | NR | Persistence 12-month (≤ refill 30-day gap) ALN-daily: 60/137 (43.7%), HR = 1.8 (95% CI 1.41 to 2.3) RIS-daily: 31/71 (44.1%), HR = 1.55 (95% CI 1.12 to 2.16) ALN-weekly (branded): 1145/1931 (59.3%), HR = 1 (95% CI 0.89 to 1.12) ALN-weekly (generic, ref.): 1742/3030 (57.5%) RIS-weekly (branded): 1887/3083 (61.2%), HR = 0.92 (95% CI 0.84 to 1.01) RIS-weekly (generic): 36/73 (48.9%), HR = 1.04 (95% CI 0.75 to 1.45) IBN-monthly: 63/108 (58.5%), HR = 0.93 (95% CI 0.69 to 1.25) |
| Wade et al., 2012 | Retr. | USA | 33,558 (total population)/F (94)/59.5 | P (7.22) | ALN; IBN; RIS | 10 mg, 70 mg; 5 mg, 35 mg; 150 mg, 3 mg/oral; IV/daily; weekly; monthly, quarterly | P (14.53) | P (52.5) | Mean 12-month MPR (SD), n ALN: 0.58 (0.35), n = 18,328 IBN: 0.57 (0.36), n = 5063 RIS: 0.58 (0.36), n = 10,167 Mean 24-month MPR (SD), n ALN: 0.50 (0.36), n = 11,232 IBN: 0.47 (0.35), n = 2492 RIS: 0.50 (0.36), n = 6398 | NR |
| Weiss et al., 2007 | Retr. | USA | 165,955/F (100)/ALN: 67.3 (11); IBN: 66.6 (10.6); RIS: 67.1 (11) | NR | ALN; IBN; RIS | 10 mg, 70 mg; 150 mg; 35 mg/oral/weekly; monthly | NR | NR | NR | Persistence in days (SD), (refill gap ≤ 30 days), HR (95% CI); OR (discontinuation) ALN: 116 (121), HR = ref.; OR = ref. IBN: 98 (113), HR = 1.098, p < 0.0001; OR = 1.383, p < 0.0001 RIS: 113 (120), HR = 1.02, p = 0.0003; OR = 1.065, p < 0.0001 Persistence in days (SD), (refill gap ≤ 45-day) ALN: 129 (128) IBN: 114 (124) RIS: 124 (127) Persistence in days (SD), (refill gap ≤ 60-day) ALN: 136 (131) IBN: 121 (128) RIS: 131 (130) |
| Xu et al., 2013 | Retr. | USA | 36,855/F (≈> 90)/commercial: 58.6 (6.4) l MAPD: 73.6 (7.6) | Commercial: 8.6; MAPD: 15.2 | ALN; IBN; RIS | NR | NR | Commercial: 38.1; MAPD: 55.5 | NR | Discontinuation at 36 months (%, total n) (refill gap ≥ 90-day, commercial database) ALN (gen.): 55.8, n = 678 ALN (br.): 57.1, n = 2429 IBN: 66.4, n = 1341 RIS: 55.2, n = 1948 Discontinuation at 36 months (%, total n) (refill gap ≥ 90-day, MAPD database) ALN (gen.): 51.6, n = 7692 ALN (br.): 57, n = 11,395 IBN: 67.4, n = 3483 RIS: 64, n = 7889 |
| Yan et al., 2009 | RCT | China | 560/F (100)/ALN: 65.19 (6.47); PLB: 64.66 (5.87) | NP | ALN; PLB | 70 mg/oral/weekly | NP | P (100) | NR | Discontinuation (n/N, total), 12 months ALN: 53/280 PLB: 42/280 Discontinuation due to AEs (n/N, total), 12 months ALN: 28/280 PLB: 19/280 Discontinuation due to other reasons (n/N, total), 12 months ALN: 25/280 PLB: 23/280 |
| Zambon et al., 2008 | Retr. | Italy | 11,863/F (100)/72 | P (14) | ALN; RIS | 10 mg, 70 mg; 5 mg, 35 mg/oral/daily, weekly | P (19) | P (100) | NR | Discontinuation HR (95% CI) (refill gap ≥ length of time covered by a given dispensation) ALN: ref. RIS: 0.762 (0.695 to 0.836), p < 0.05 |
| Zhang et al., 2015 | RCT | China | 219/F (100)/ALN: 65.6 (8.0); PLB: 64.8 (7.4) | NP | ALN; PLB (calcitriol) | 70 mg/oral/weekly | NR | P (NR) | NR | Discontinuation (n/N, total), 12 months ALN: 16/111 PLB: 7/108 Discontinuation due to AEs (n/N, total), 12 months ALN: 8/111 PLB: 1/108 Discontinuation due to other reasons (n/N, total), 12 months ALN: 8/111 PLB: 6/108 |
| Zhou et al., 2020 | RCT | China | 123/F (25.2)/83.54 (2.99) | NR | ALN; PLB | 70 mg/oral/weekly | NP | NP | Compliance (100% use of drug), 18 months ALN: 3/62 PLB: 8/61 | Discontinuation (n/N, total), 18 months ALN: 3/62 PLB: 8/61 |
| Ziller et al., 2012 | Retr. | Germany | 268,568/F ALN-daily: 65.9; ALN-weekly: 85.8; ALN-vit. D: 85.6; IBN-oral: 92; IBN-IV: 86.7; RIS-daily: 85.5; RIS-weekly: 87.4; RIS-calcium: 88.6; ZOL: 55.4/ALN-daily: 73.4; ALN-weekly: 74.7; ALN-vit. D: 74.1; IBN-oral: 72.5; IBN-IV: 72; RIS-daily: 75.4; RIS-weekly: 74.2; RIS-calcium: 74; ZOL: 70.4 | NR | ALN; IBN; RIS; ZOL | 10 mg, 70 mg; 150 mg; 3 mg; 5 mg, 35 mg; 5 mg/oral; IV/daily, weekly, monthly, annually | NR | NR | MPR (mean in %) ALN (daily): 33 ALN (weekly): 57 ALN + vit. D: 53 IBN-oral: 62 IBN-IV: 70 RIS (daily): 47 RIS (weekly): 53 RIS + cal.: 58 ZOL: NA MPR ≥ 80% ALN (daily): 15.8 ALN (weekly): 37.3 ALN + vit. D: 32.6 IBN-oral: 44.5 IBN-IV: 53 RIS (daily): 28.8 RIS (weekly): 30.2 RIS + cal.: 38.8 | Persistence in days (mean) ALN (daily): 141 ALN (weekly): 239.8 ALN + vit. D: 218.7 IBN-oral: 256.4 IBN-IV: 278.6 RIS (daily): 190.9 RIS (weekly): 218.7 RIS + cal.: 238.7 ZOL: 365 Post 12-month persistence (n/N, %), refill gap ≥ 6 months ZOL: 8617/13,132, 65.62% IBN-IV: 7089/12,525, 56.6% IBN-oral: 7326/14,426, 50.78% ALN (weekly): 69,663/155,637, 44.76% ALN (plus vit. D): 5538/14,666, 37.76% ALN (daily): 583/3359, 17.34% RIS (plus calcium): 9010/21,309, 42.28% RIS (weekly): 8481/24,126, 35.15% RIS (daily): 335/1107, 30.26% |
Overall, for persistence, 16,577 participants were included in the NMAs of RCTs, and 985,484 BP users were included in the NMAs of retrospective observational studies.
Networks’ structure and geometry
Two network plots comparing BP effects on the absolute numbers of dropouts were created. Data on dropouts at 12 months provided six closed loops of evidence (see Appendix 3, Figure 14). Overall, 30 two-arm and 1 three-arm studies were included in the analysis, resulting in a total of 10,419 participants. The most studied treatment was ALN (nstudies = 16), while PLB was used as a comparator in 24 studies. Data on dropouts at 24 months provided four closed loops of evidence (see Appendix 4, Figure 15). Overall, 21 two-arm and 1 three-arm studies were included in the analysis, resulting in a total of 6158 participants. The most studied treatment was ZOL (nstudies = 10), while PLB was used as a comparator in 19 studies. One network was created for discontinuation data drawn from observational studies (see Appendix 5, Figure 16). Overall, 8 two-arm, 12 three-arm and 4 five-arm studies were included in the analysis. The most common treatments were ALN and RIS, with each contributing 23 arms in the analysis. Studies’ characteristics and risk of bias within individual studies are shown in Table 9.
Of the included trials, 31 were conducted in North America or in multiple countries. Overall, 38 trials exclusively targeted female participants, while in 21 trials, most of the participants fulfilled the criteria of osteoporosis. In total, the overall risk of bias was high in 18 trials. The majority of observational studies adopted a retrospective design, while three of them adopted a prospective comparative design. Twenty observational studies were conducted in Europe, and 18 studies were conducted in the USA. In 14 studies, the majority of participants fulfilled the criteria of osteoporosis. Overall, three studies received a moderate risk-of-bias rating, two received a critical risk-of-bias rating and the rest received a serious risk-of-bias rating.
Synthesis of results on persistence: measured using dropouts in randomised controlled trials
A NMA was used to compare the effects of ALN, RIS, ZOL and IBN-oral relative to PLB on the total number of dropouts at 12 months. Overall, data were available from 30 two-arm and 1 three-arm RCTs. The network provided nine direct treatment comparisons. Each of the direct comparisons between ALN versus ZOL and RIS versus IBN-oral was informed by one small study. Eight contrasts were checked for inconsistency between direct and indirect evidence. None of the comparisons showed significant evidence of inconsistency, as assessed using Bayesian p values (p > 0.05). The model fitted the data relatively well (difference < 3), with a Dres of 64.8 being close to the number of data points included in the analysis, which was 63 (DIC = 369). The between-study SD was estimated to be 0.16 (95% CrI 0.009 to 0.41), implying mild heterogeneity in treatment effects between RCTs. Users of ZOL and RIS were less likely to drop out compared to PLB users, with none of these effects being statistically significant. The lowest likelihood of dropping out was detected in ZOL users OR = 0.73 (95% CrI 0.51 to 1.05; probability: 0.88; SUCRA: 0.95).
A NMA was used to compare the effects of ALN, RIS, ZOL and IBN-oral relative to PLB on the total number of dropouts at 24 months. Overall, data were available from 21 two-arm and 1 three-arm RCTs. The network provided eight direct treatment comparisons. Each of the direct comparisons between ALN versus IBN, ALN versus RIS and RIS versus IBN-oral were informed by one small study. Three contrasts were checked for inconsistency between direct and indirect evidence. None of the comparisons showed significant evidence of inconsistency, as assessed using Bayesian p values (p > 0.05). The model fitted the data well, with a Dres of 45.51 being close to the number of data points included in the analysis, which was 45 (DIC = 276.7). The between-study SD was estimated to be 0.34 (95% CrI 0.09 to 0.64), implying mild to moderate heterogeneity in treatment effects between RCTs but with reasonable uncertainty. Users of ALN, RIS and IBN-oral were less likely to drop out compared to PLB users, with none of these effects being statistically significant. The lowest likelihood of dropping out was detected in IBN-oral users OR = 0.72 (95% CrI 0.31 to 1.66; probability: 0.54; SUCRA: 0.72).
Synthesis of results on persistence: measured using discontinuation of treatment data from observational studies
A NMA was used to compare the effects of RIS, ZOL, IBN-oral and IBN-IV relative to ALN on the absolute number of people who discontinued their BP treatments. Overall, data were available from 24 retrospective observational studies. The model fitted the data well, with a Dres of 73.27 being close to the number of data points included in the analysis, which was 73 (DIC = 762.5). The between-study SD was estimated to be 0.24 (95% CrI 0.19 to 0.31), implying mild heterogeneity in treatment effects between observational studies with reasonable uncertainty. Users of ZOL and IBN-IV were less likely to discontinue compared to ALN, with the effects of the former being statistically significant (Table 10). The lowest likelihood for discontinuation was detected in ZOL users HR = 0.73 (95% CrI 0.61 to 0.88; probability: 0.88; SUCRA: 0.97). Heterogeneity of effects was explored by undertaking a post hoc meta-regression on the absolute number of discontinuers using refill-gap as a moderator variable. Although slightly decreased in magnitude, the direction of effects remained the same. The model fit remained almost the same, with a Dres of 72.63 (DIC: 755.9). The between-study SD was estimated to be 0.29 (95% CrI 0.20 to 0.42), implying mild heterogeneity in treatment effects between RCTs with reasonable uncertainty. Higher medication effects on discontinuation were detected in participants with longer refill gap thresholds, although the results were not statistically significant β = −0.23 [95% confidence interval (CI) −0.72 to 0.21].
| ZOL | 0.81(0.47 to 1.39) | IBN-oral | - | ZOL | - | |||||||||||
| 0.76(0.53 to 1.11) | RIS | 0.97(0.66 to 1.5) | 0.86 (0.37 to 2.05) | RIS | 0.84(0.55 to 1.30) | 0.86(0.68 to 1.09) | IBN-IV | - | ||||||||
| 0.73 (0.51 to 1.05) | 0.95(0.72 to 1.26) | PLB | 0.84 (0.36 to 2.00) | 0.97 (0.56 to 1.74) | ALN | 0.78(0.41 to 1.52) | 0.73(0.61 to 0.88) | 0.84(0.68 to 1.06) | ALN | |||||||
| 0.69(0.49 to 1.02) | 0.90(0.69 to 1.20) | 0.94(0.75 to 1.20) | ALN | 0.72 (0.33 to 1.66) | 0.84 (0.57 to 1.24) | 0.86 (0.53 to 1.37) | PLB | 0.73(0.6 to 0.88) | 0.84(0.67 to 1.06) | 0.99(0.87 to 1.13) | IBN-oral | |||||
| 0.64 (0.39 to 1.02) | 0.83 (0.54 to 1.23) | 0.87(0.60 to 1.24) | 0.92(0.63 to 1.27) | IBN-oral | 0.67 (0.28 to 1.68) | 0.78(0.47 to 1.31) | 0.80 (0.47 to 1.33) | 0.92 (0.66 to 1.32) | ZOL | 0.67(0.56 to 0.80) | 0.77(0.62 to 0.97) | 0.91(0.82 to 1.01) | 0.91(0.80 to 1.04) | RIS |
Discussion
Updated review
Overall, 44 trials provided data for femoral neck BMD, whereas 27 and 19 trials provided data for vertebral and non-vertebral fractures, respectively. Only 14 and 10 trials provided data for hip and wrist fractures, respectively. ZOL was found to be the most effective treatment in preventing the occurrence of vertebral fractures and increasing femoral neck BMD. ZOL was also found to be comparably effective to RIS and ALN in preventing non-vertebral fractures and hip fractures, respectively. ZOL’s effects in preventing hip and vertebral fractures and increasing femoral neck BMD were found to be clinically significant. In addition, treatment effects in preventing vertebral fractures were found to be stronger in people with osteoporosis compared to PLB. Uptake of ZOL was also found to be accompanied by more frequently reported adverse events; however, these events are likely to be short-lived. Based on these updated estimates, ZOL could be considered as the first-line treatment for people who experience or are at increased risk of fragility fractures.
These findings arguably have important implications for clinical decision-making in terms of the preferred therapeutic approach for people with varying fracture risk. It has recently been suggested that anabolic treatments should be preferred as the first-line treatment for people who are at high risk for developing osteoporotic fractures.151 Although recent evidence has shown that anabolic treatment is more effective than BP in reducing fracture risk in females who are at high risk of developing fractures,152,153 its effectiveness has only been tested against oral BP. There is therefore an urgent need for future comparative studies to test the effectiveness of anabolic treatments versus ZOL in reducing the fracture risk in high-risk populations. This becomes more apparent when the imminent fracture risk and the need to expedite clinical decision-making154,155 are taken into account. Based on our findings, ZOL seems to be a promising treatment that could decrease the imminent fracture risk for high-risk populations within 24 months after administration. Future studies should investigate whether ZOL or anabolic treatments are more effective in reducing imminent fracture risk in high-risk populations.
Adherence review
For persistence, results from the NMA from RCTs showed that ZOL users may be less likely to drop out from trials at 12 months, although these effects were marginally non-significant. Results from the NMA using data from the observational studies showed that ZOL and IBN-IV users were less likely to discontinue their treatment over time, with ZOL users being statistically significantly more persistent compared to oral BP users. Data drawn from the vote-counting synthesis were in line with the results of NMAs, where ZOL and IBN-IV users were more likely to persist with their treatment, with ZOL users being more persistent compared to their IBN-IV counterparts. Users of ALN and RIS showed comparable persistence rates; however, when we restricted our analysis to weekly administration, ALN users were found to be more likely to persist to treatment over time. Due to the paucity of data and the heterogeneity in reporting compliance data, we were unable to perform NMAs, but synthesis based on vote counting found that compliance to ZOL was greater within 24 months after the initiation of their treatment. Users of IBN-IV were found to be more compliant compared to IBN-oral users. Users of ALN were found to be more compliant than RIS users, while mixed evidence was observed in the comparison between ALN and IBN-oral users.
These findings have important implications for clinical practice and future research. In general, persistence to BP treatment was found to decrease after 12 months, stressing the need to address adherence barriers according to BP treatment and people with different clinical profiles. Nevertheless, ZOL users were found to be less likely to discontinue their treatment over time, and they showed higher compliance rates. These findings are partly in line with the results from the dropout NMA at 12 months. Without ignoring the interplay of individual and contextual factors, which affect participation and adherence in clinical trials,156,157 we can assume that most ZOL users are likely to receive at least two infusions before discontinuing their treatment. The use of ZOL has been generally recommended for at least 3 years5 and, although reduced adherence rates have been observed in ZOL users after the first year,158 simpler drug regimens can improve adherence rates.159 Results of vote-counting synthesis on oral BPs were partly in line with the NMA results. ALN and RIS users showed comparable persistence rates; however, ALN users were found to be more compliant than their RIS counterparts. When we restricted our synthesis to weekly administration of both BP, weekly ALN users were found to be more persistent to treatment compared to RIS weekly users. Given that ALN is the most widely prescribed medication, clinical decision-making should consider, alongside its clinical effectiveness, ways in which ALN users could be assisted to receive medication properly and remain on treatment long-term.
Strengths and limitations
Updated review
These NMAs provide updated estimates regarding the BP effect in preventing the occurrence of fractures. This updated systematic review has several strengths. First, this review includes a robust search strategy with clearly demarcated eligibility criteria, covering a wide range of databases, trial registries and grey literature. Second, this review employed gold-standard methods in analysing, reporting and assessing the quality of findings, which in turn facilitates clinical decision-making. Inevitably, this review also has some limitations. First, treatment networks for hip and wrist fractures were sparse, something that might limit the generalisation of our conclusions regarding BPs’ effects on those outcomes. Second, none of the included studies had tested IBN-IV against any other BP or PLB, preventing the provision of updated estimates regarding IBN-IV effectiveness. Third, there was scarcity of data regarding BPs’ effects on male populations and populations with exposure to GC. Fourth, there were a large number of studies with an overall high-risk rating in the risk-of-bias assessment.
Adherence review
This systematic review has several strengths. First, this review includes a robust search strategy, covering a wide range of databases, trial registries and grey literature. Second, this systematic review employed gold-standard methods in conducting, reporting and assessing the credibility of findings. Third, this systematic review included both RCTs and observational studies, adopting a combined approach to synthesise data. Inevitably, this review also has some limitations. First, participants’ persistence on BP treatments in RCTs was assessed by using the total number of dropouts as a proxy measure. Given that this was the only way to capture discontinuers in RCTs, dropout NMA findings should be interpreted under this limitation. Second, persistence in the NMA of observational studies was assessed as the absolute number of discontinuers per BP treatment based on varying refill gaps and without accounting for the censored follow-up time. Third, due to the scarcity of data on males, a subgroup analysis of persistence rates between males and females was not conducted. Fourth, compliance was indirectly assessed by measuring treatment continuity based on different measures. Although a NMA would be more informative, vote-counting synthesis is well suited in the presence of incomplete and highly heterogeneous data in both observational studies and RCTs. Fifth, this review did not assess the comparative effectiveness of BP against monoclonal antibody and anabolic medications. Sixth, the paucity of data precluded the subgroup analysis between participants receiving BP for primary prevention and those receiving BP for secondary prevention purposes.
Conclusion
Zoledronate was found to be the most effective BP compared to ALN, RIS and IBN-oral for reducing the risk of fragility fracture. Adherence was higher in intravenously administered BP users. Clinical decision-making could be facilitated by taking into account adherence patterns in BP users who are at increased risk of fractures. Depending on its cost-effectiveness, ZOL could be considered as a first-line option for people at increased risk of subsequent fractures.