Abstract
Objectives
Osteoporosis has become an increasing concern for older people as it may potentially lead to osteoporotic fractures. This study is designed to assess the efficacy and safety of ten therapies for post-menopausal women using network meta-analysis.
Methods
We conducted a systematic search in several databases, including PubMed and Embase. A random-effects model was employed and results were assessed by the odds ratio (OR) and corresponding 95% confidence intervals (CI). Furthermore, with respect to each outcome, each intervention was ranked according to the surface under the cumulative ranking curve (SUCRA) value.
Results
With respect to preventing new vertebral fractures (NVF), all ten drugs outperformed placebo, and etidronate proved to be the most effective treatment (OR 0.24, 95% CI 0.14 to 0.39). In addition, zoledronic acid and parathyroid hormone ranked higher compared with the other drugs. With respect to preventing clinical vertebral fractures (CVF), zoledronic acid proved to be the most effective drug (OR = 0.25, 95% CI 0.08 to 0.92), with denosumab as a desirable second option (OR = 0.48, 95% CI 0.22 to 0.96), when both were compared with placebo. As for adverse events (AE) and severe adverse events (SAE), no significant difference was observed. According to SUCRA, etidronate ranked first in preventing CVF; parathyroid hormone and zoledronic acid ranked highly in preventing NVF and CVF. Raloxifene was safe with a high rank in preventing AEs and SAEs though performed unsatisfactorily in efficacy.
Conclusions
This study suggests that, taking efficacy and safety into account, parathyroid hormone and zoledronic acid had the highest probability of satisfactory performance in preventing osteoporotic fractures.
Cite this article: G. Wang, L. Sui, P. Gai, G. Li, X. Qi, X. Jiang. The efficacy and safety of vertebral fracture prevention therapies in post-menopausal osteoporosis treatment: Which therapies work best? a network meta-analysis. Bone Joint Res 2017;6:452–463. DOI: 10.1302/2046-3758.67.BJR-2016-0292.R1.
Article focus
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This study is designed to assess the efficacy and safety in the prevention of vertebral fractures of ten therapies for post-menopausal osteoporosis using network meta-analysis.
Key messages
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Parathyroid hormone and zoledronic acid might have the highest probability of satisfactory performance in prevention of vertebral fractures in post-menopausal osteoporosis.
Strengths and limitations
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Our study fills the void of existing research and most of our results fall in line with existing clinical studies and may have promising potential clinical implications. However, one limitation of our study is the small number of relevant studies available for reference and some key comparisons were missing in the analysis of CVF and SAE
Introduction
Osteoporosis has become an increasing concern for the older population. It is a disease characterised by decreased bone strength and may lead to osteoporotic fractures.1 It may also significantly affect health and quality of life, and create a heavy burden for both families and society in general. A previous study demonstrated that the annual incidence rate of fractures increases with age, especially among post-menopausal women who are more vulnerable to osteoporosis due to oestrogen deficiency.2 According to a survey, about 1.5 million fragility fractures are attributed to osteoporosis every year in the United States, and about half of these are vertebral fractures (VF).3 Patients with a previous VF have a higher risk of a second VF within the next year. Therefore, the primary goal of osteoporosis treatment is to reduce the incidence rate of new vertebral fractures (NVF).
Several therapies are currently available for the prevention and treatment of post-menopausal osteoporosis (PMO) including oral bisphosphonates (e.g. alendronate, (ALE)), oestrogen replacement therapy, selective oestrogen receptor modulator (e.g. risedronate (RIS)), and calcitonin and biological agents (e.g. denosumab (DEN)).4 However, the long-term use of oestrogen replacement therapy significantly increases the risk of breast and ovarian cancer,5 and calcitonin is not widely used in clinical management. Therefore, these two therapies were not included in this study.
Oral bisphosphonates are the most common treatment for osteoporosis. In the United Kingdom, about 10% of women aged 70 years or above were treated with bisphosphonates in 2005.6 The National Osteoporosis Guideline Group and the National Institute for Clinical Excellence, both in the United Kingdom, recommend ALE as the first choice of therapy for reducing fracture risk. Ibandronate (IBA) and RIS are recommended as secondary options.7 In addition, clodronate (COL) has demonstrated its anti-resorptive efficacy in various other diseases related to the increased resorption of bone and the prevention of PMO.8,9 Etidronate (ETI), a first-generation bisphosphonate which inhibits resorption, has the potential to inhibit mineralisation and cause osteomalacia.10 Studies on the long-term use of ALE have shown that it retains the benefit of successfully reducing bone loss and VF.11 Additionally, strontium ranelate (STR) is another anti-osteoporotic agent which can stimulate bone formation and reduce resorption.12 DEN is a potent agent which can reduce the risk of NVF by increasing bone density.13 Raloxifene (RAL) increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture.14 The beneficial effects of parathyroid hormone (PTH) treatment have also been clearly demonstrated through randomised clinical trials (RCT)15 and its few adverse events (AE) make it a good candidate for various uses such as PTH treatment, leading to induction bone formation without inducing bone resorption.16
There have been many RCTs conducted on these therapies in order to identify the most effective method in preventing NVF in post-menopausal women. Several studies attempting to compare the results of pairwise meta-analyses in regard to the prevention and safety of different treatments can also be found in the current literature.17-19 However, it is still difficult to reach a conclusion due to the limitations of the traditional pairwise meta-analysis (i.e. there is no concise synthesis of the data). Furthermore, the reduction of fracture risk is mainly demonstrated in placebo-controlled trials, and head-to-head comparisons of different agents are rare.
A network meta-analysis (NMA) can estimate the differences in efficacy and safety of various treatments.20 This can provide relevant comparative evidence that compares all treatments by linking the treatments in a network of trials. The main objective of this study was to assess the efficacy and safety of ten commonly used therapies to determine the optimal treatment for post-menopausal women who are at risk for VF (available agents include ALE, COL, DEN, ETI, IBA, PTH, RAL, RIS, STR and zoledronic acid (ZOL)).
Materials and Methods
Data search strategy
Our research began with a systematic search of several databases including PubMed and Embase, as well as the Cochrane library, ClinicalTrials.gov, CNKI, and Wanfang databases. The search only included papers written in English. The keywords for the search included: “post-menopausal osteoporosis”, “randomised clinical trials”, “alendronate”, “raloxifene”, “denosumab”, “parathyroid hormone”, “ibandronate”, “risedronate”, “clodronate”, “etidronate”, “zoledronic acid” and “strontium ranelate”. More details can be seen in supplementary Table i.
In order to ensure the high quality of selection and accuracy in our study, two reviewers independently identified the title and abstract of each eligible paper. Only papers whose title and abstract fit the inclusion criteria passed the initial screening. After initial filtering, the full texts of remaining papers were further examined. Studies with insufficient information, irrelevant outcomes or lack of comparison with other interventions were removed. Any disagreement was resolved through discussion until consensus was reached.
Inclusion and exclusion criteria
Studies were included in the network meta-analysis if they met all of the following criteria: 1) the study was designed as an RCT; 2) subjects were post-menopausal women with osteoporosis; 3) the study was designed to compare the effects of the following drugs with placebo (PLA) or between each other: ALE, COL, DEN, ETI, IBA, PTH, RAL, RIS, STR, and ZOL; 4) at least one of the following outcomes was included as the primary or secondary endpoint: NVF; clinical vertebral fractures (CVF); AEs and serious adverse events (SAE). Studies were excluded if: 1) not all women involved in the study were post-menopausal; 2) men were included in the study and could not be separated from women; 3) the treatment contained drugs that were not mentioned above and could not be separated.
Data extraction and statistical analysis
The full text of each identified study was then further evaluated. The treatment data, consisting of dosing regimen, treatment duration, blinding condition, trial size and outcomes of the study, were extracted; patients’ mean age, and year of menopause were also collected. Firstly, a meta-analysis with a random-effects model was performed to compare different interventions with PLA directly by R Software (Version 3.2.3; R Foundation for Statistical Computing, Vienna, Austria). The inter-group discrepancies were assessed by odds ratio (OR) with a corresponding 95% confidence interval (CI). Heterogeneity was assessed using Cochran’s Q test and the chi-squared test. Heterogeneity across the studies was considered to be significant if p < 0.05 for the Q test or chi-squared > 50%. We then used a fixed-effects model (Mantel-Haenszel method)21 and a random-effects model (DerSimonian-Laird method)22 to minimise the effect of heterogeneity. Moreover, one-way sensitivity analysis was also used to evaluate the robustness of the results.
In addition, a NMA combining direct and indirect results was carried out in R Software (Version 3.2.3). The results were demonstrated by cumulative OR and corresponding 95% CI, which represents the interval in the domain of a posterior probability distribution.23 As shown in Spieglhalter et al,24 we employed a random-effects model within a Bayesian framework, and a mesh-like diagram was drawn based on incorporated studies. Meanwhile, we performed a probabilistic analysis to give a probable ranking for each intervention, which was weighted by the SUCRA.25 The sum of the ranking possibility of each treatment is the SUCRA. The higher the SUCRA of a given treatment, the more efficient or safe it is.
Results
Study characteristics
The drugs involved in our study include PLA, ALE, COL, DEN, ETI, IBA, PTH, RAL, RIS, STR, and ZOL, and the endpoints include NVF, CVF, AE and SAE. Here, NVF was defined as a reduction of ⩾ 20%, with an absolute decrease of ⩾ 4 mm, in the height of any vertebral body between baseline and the end of treatment, and it was determined as our primary outcome because it occurred the most frequently in the included studies. CVF was defined as new or worsening back pain with a reduction in vertebral body height of 20% (grade 1) or more, as compared with baseline radiographs, or a reduction in vertebral body height of 25% (grade 2) or more if no baseline radiograph was available. Gastrointestinal events, hypocalcaemia, bacterial cellulitis, eczema, hypersensitivity, cardiac disorders and vascular disorders were considered as AEs of interest. A total of 1609 records were initially included in this study (Fig. 1). After removing duplicates and screening by scanning abstracts and titles, 70 studies remained. Subsequent to further exclusion, 42 studies met the criteria and were finally included in our study.4,13,14,19,26-63 Among the 42 studies, shown in Figure 2, most of the direct comparisons are between PLA and other drugs. Furthermore, DEN and ALE appeared the most frequently, as illustrated in Table I. In total, 92 904 post-menopausal women with osteoporosis were involved in our study. Most of the studies were classified as double-blind with the remaining being assessor blind, open label or unknown.
Fig. 1
Flow diagram summarising the results of study identification and selection.
Fig.
Network structures according to (a) new vertebral fractures, (b) clinical vertebral fractures, (c) adverse events, and (d) serious adverse events (ETI, eronate; COL, clodronate; PTH, parathyroid hormone; ZOL, zoledronic acid; STR, strontium ranelate; DEN, denosumab; IBA, ibandronate; RAL, raloxifene; RIS, risedronate; ALE, alendronate; PLA, placebo
Table I.
Characteristics of studies included in the network meta-analysis)
| Comparison study information | Study duration (yrs) | Blinding | Mean age (yrs) | Time after menopause (yrs) | Treatment | Regimen dosing* | Patients (n) | Outcome† |
|---|---|---|---|---|---|---|---|---|
| ALE vs PLA | ||||||||
| Liberman et al62 | 10 | √ | 64/64 | 16/17 | ALE/PLA | 5, 10, or 20 mg QD | 994 | 1,4 |
| Bone et al59 | 2 | √ | 71.1/71.1 | 24.2/22.8 | ALE/PLA | 1, 2.5, or 5 mg QD | 359 | 1,3,4 |
| Black et al61 | 3 | √ | 71/70.7 | NS | ALE/PLA | 5 to 10 mg QD | 2027 | 1,2,4 |
| Cummings et al55 | 4.2 | √ | 67.7/67.6 | NS | ALE/PLA | 5 to 10 mg QD | 4432 | 1 |
| Saag et al52 | 0.92 | √ | NS | NS | ALE/PLA | 5 mg QD | 150 | 1 |
| Adachi et al47 | 2 | √ | NS | NS | ALE/PLA | 5 mg QD | 54 | 1 |
| COL vs PLA | ||||||||
| McCloskey et al42 | 3 | √ | 67.5/67.7 | NS | COL/PLA | 800 mg QD | 593 | 1 |
| McCloskey et al35 | 3 | √ | 79.5/79.6 | NS | COL/PLA | 800 mg QD | 5592 | 1,3,4 |
| DEN vs PLA | ||||||||
| Cummings et al13 | 3 | √ | 72.3/72.3 | NS | DEN/PLA | 7808 | 1,2,3,4 | |
| Gnant et al26 | 3 | √ | NS | NS | DEN/PLA | 60 mg Q6M | 3420 | 1,3,4 |
| Bone et al31 | 3 | √ | 71.9/71.8 | 23.7/23.7 | DEN/PLA | 60 mg Q6M/60 mg Q6M | 9100 | 2,3,4 |
| ETI vs PLA | ||||||||
| Lyritis et al57 | 16 | Open label | 71.8/72.2 | 25.1/26.4 | ETI/PLA | 400 mg QD | 100 | 1 |
| Montessori et al56 | Open label | 62.1/62.9 | 3.4/3.5 | ETI/PLA | 400 mg QD | 71 | 1 | |
| Adachi et al60 | 1 | √ | NS | NS | ETI/PLA | 400 mg QD | 70 | 1,4 |
| Storm et al63 | √ | 67.8/68.9 | 21.2/21.9 | ETI (Cyclic)/PLA | 400 mg QD | 66 | 1 | |
| Shiota et al45 | NS | 60.7/62.7 | 13.8/15.3 | ETI (Cyclic)/PLA | 200 mg QD | 40 | 1 | |
| IBA vs PLA | ||||||||
| Chesnut et al43 | 3 | √ | 69/69 | 20.9/20.8 | IBA/PLA | 2.5 mg QD, or 20 mg QOD | 2946 | 1,2,3,4 |
| Chesnut et al40 | 3 | √ | 68.7/68.8 | 20.8/20.8 | IBA/PLA | 2.5 mg QD, or 20 um Q2D | 2929 | 1,2,3,4 |
| PTH vs PLA | ||||||||
| Neer et al46 | 1.75 | √ | 70/69 | NS | PTH/PLA | 20, 40 mcg QD | 1637 | 1 |
| Greenspan 200736 | 1.5 | √ | NS | NS | PTH/PLA | 100 ug QD | 471 | 2 |
| RAL vs PLA | ||||||||
| Lufkin et al54 | 1 | √ | 69.9/68.2 | 22/22.2 | RAL/PLA | 60, or 120 mg QD | 143 | 1 |
| Ettinger et al14 | 4 | √ | 65/65 | 17-21/18-21 | RAL/PLA | 60, or 120 mg QD | 6828 | 1 |
| Morii et al44 | 1 | √ | 65.2/64.7 | 15.2/15.8 | RAL/PLA | 60 mg QD/120 mg QD | 202 | 1,3,4 |
| Ensrud et al34 | 5.6 | √ | 67.5/67.5 | NS | RAL/PLA | 60 mg QD | 10101 | 1 |
| RIS vs PLA | ||||||||
| Fogelman et al50 | 2 | √ | 65/64 | 18/17 | RIS/PLA | 2.5, or 5 mg QD | 543 | 1,3,4 |
| Hooper et al39 | √ | 53/52.6 | 46.1w/46.6w | RIS/PLA | 2.5, or 5 mg QD | 383 | 1,3,4 | |
| Palomba et al38 | 1 | Assess-or blind | 52.3/51.4 | 16.4w/17.5w | RIS/PLA | 35 mg QW | 81 | 1 |
| Reginster et al49 | √ | 71/71 | 24/25 | RIS/PLA | 2.5, or 5 mg QD | 1226 | 1,3,4 | |
| Harris et al51 | √ | 69/68 | 24/24 | RIS/PLA | 5 mg QD | 1641 | 1,3,4 | |
| Wallach et al48 | 1 | √ | 64.3/64.2 | NS | RIS/PLA | 5, or 10 mg QD | 255 | 1 |
| Mortensen et al53 | √ | 52.1/51.3 | 3 | RIS/PLA | 5 mg QD | 111 | 1 | |
| Clemmesen et al58 | √ | 68/70 | 18 | RIS/PLA | 2.5 mg QD | 132 | 1 | |
| STR vs PLA | ||||||||
| Meunier et al41 | 3 | √ | 69.2/69.4 | 21.6/22.1 | PLA/STR | 2 g QD | 1649 | 1,4 |
| Reginster et al32 | 5 | √ | 76.8/76.7 | 28.4/28.5 | PLA/STR | 2 g QD | 5091 | 1,3,4 |
| ZOL vs PLA | ||||||||
| Black et al37 | 3 | √ | 73.1/73 | NS | ZOL/PLA | 5 mg QY | 7765 | 1,2,3,4 |
| Black et al27 | 3 | √ | 78/78.1 | NS | ZOL/PLA | 5 mg QY | 190 | 1,4 |
| Popp et al28 | 3 | √ | 76.5/77 | NS | ZOL/PLA | 5 mg QY | 110 | 1,3,4 |
| RAL vs ALE | ||||||||
| Recker et al4 | √ | 65.5/65.7 | 18.5/19 | RAL/ALE | 60 mg QD/10 mg QD | 1423 | 1,2,4 | |
| Iwamoto et al33 | 1 | √ | 70.3/68.5 | NS | RAL/ALE | 60 mg QD/5 mg QD | 122 | 1,4 |
| RIS vs ALE | ||||||||
| Thomas et al29 | 1.25 | NS | 75/76 | NS | RIS/ALE | 11007 | 1 | |
| RIS vs ETI | ||||||||
| Fukunaga19 | √ | 63.1/62.1 | 13.8/12.8 | RIS/ETI (Cyclic) | 2.5 mg QD/200 mg QD | 209 | 1,4 | |
| DEN vs IBA | ||||||||
| Recknor et al30 | 1 | NS | 67.2/66.2 | 20.4/19.7 | DEN/IBA | 60 mg Q6M | 833 | 1,4 |
-
*
Regimen dosing: QD, once a day; QW, once a week; QM, once a month; QY, once a year; IU, International Unit
-
†
Outcome 1, New vertebral fractures; 2, Clinical vertebral fractures; 3, Serious adverse events; 4, Adverse events. NS, not specified
-
ALE, alendronate; PLA, placebo; COL, clodronate; DEN, denosumab; ETI, eronate; IBA, ibandronate; PTH, parathyroid hormone; RAL raloxifene; RIS, risedronate; STR, strontium ranelate; ZOL zoledronic acid
NVF
As shown in Figure 3, we found that all ten therapies were more effective than placebo in terms of NVF. Specifically, among the ten therapies, ETI outperformed ALE, COL, IBA, RAL, RIS, STR and ZOL. ZOL performed better than ALE, IBA, RAL, RIS and STR, and PTH achieved a better performance than ALE, IBA, RAL, RIS and STR. Accordingly, ETI, ZOL and PTH came top in overall NVF efficacy. On the other hand, RAL and STR were relatively unsatisfactory because their SUCRA were inferior to many drugs.
Fig. 3
Forest plot of new vertebral fractures (ETI, eronate; COL, clodronate; PTH, parathyroid hormone; ZOL, zoledronic acid; STR, strontium ranelate; DEN, denosumab; IBA, ibandronate; RAL, raloxifene; RIS, risedronate; ALE, alendronate; PLA, placebo).
CVF
In terms of outcome CVF (Fig. 4 and supplementary Table ii), none of the ten therapies showed a statistically significant superiority to placebo since all 95% CIs include the value one (no effect). Similarly, comparison between different therapies did not exhibit any statistically significant difference.
Fig. 4
Forest plot of clinical vertebral fractures (COL, clodronate; PTH, parathyroid hormone; ZOL, zoledronic acid; DEN, denosumab; IBA, ibandronate; RAL, raloxifene; ALE, alendronate; PLA: placebo).
AEs and SAEs
According to Figure 5, Figure 6 and supplementary Table ii, the results of AEs and SAEs were similar to CVF, in that the performance of all ten therapies in triggering AEs and SAEs did not differ significantly from that of PLA and between different therapies.
Fig. 5
Forest plot of adverse events (ETI, eronate; COL, clodronate; ZOL, zoledronic acid; STR, strontium ranelate; DEN, denosumab; IBA, ibandronate; RAL, raloxifene; RIS, risedronate; ALE, alendronate; PLA, placebo).
Fig. 6
Forest plot of serious adverse events. COL, clodronate; ZOL, zoledronic acid; STR, strontium ranelate; DEN, denosumab; IBA, ibandronate; RAL, raloxifene; RIS, risedronate; ALE, alendronate; PLA, placebo.
Comparisons between direct and indirect evidence
The node-splitting method (a method comparing direct and indirect evidence for a particular comparison of treatments) and Bayesian p-values were used to report inconsistencies between direct comparison and indirect comparison of our results (Fig. 7). The overall consistency condition was satisfactory except for the outcome of AEs. Within AEs, inconsistency existed in the comparisons between DEN and PLA, IBA and PLA, and IBA and DEN, with corresponding p values of 0.028, 0.026 and 0.026, respectively.
Fig. 7
Node-splitting results for new vertebral fractures, clinical vertebral fractures, adverse events and serious adverse events (ETI, eronate; DEN, denosumab; IBA, ibandronate; RAL, raloxifene; RIS, risedronate; ALE, alendronate; PLA, placebo).
Relative ranking of ten interventions
In this section, we employed SUCRA to give a probability rank for ten interventions. The results were shown in Figure 8 and Table II. From these results, the following conclusions could be made: in terms of the primary outcome of NVF, ETI was the best intervention due to its top probability ranking, followed sequentially by ZOL and PTH. With respect to CVF, ZOL ranked top, followed by DEN. In terms of AEs and SAEs, the performance of these interventions was hard to distinguish except for RAL, which indicated that most therapies were less likely to cause AEs and SAEs.
Fig.
SUCRA of new vertebral fractures (a) clinical vertebral fractures (b) adverse events (c) and serious adverse events (d) (ETI, eronate; COL, clodronate; PTH, parathyroid hormone; ZOL, zoledronic acid; STR, strontium ranelate; DEN, denosumab; IBA, ibandronate; RAL, raloxifene; RIS, risedronate; ALE, alendronate; PLA, placebo).
Table II.
SUCRA values of all studied interventions with regard to NVF, CVF, AEs, and SAEs
| Outcome | PLA | ALE | COL | DEN | ETI | IBA | PTH | RAL | RIS | STR | ZOL |
|---|---|---|---|---|---|---|---|---|---|---|---|
| NVF | 0.001 | 0.402 | 0.439 | 0.785 | 0.916 | 0.427 | 0.813 | 0.285 | 0.450 | 0.113 | 0.85 |
| CVF | 0.119 | 0.473 | 0.349 | 0.576 | - | 0.534 | 0.584 | 0.507 | - | - | 0.854 |
| AEs | 0.654 | 0.756 | 0.227 | 0.772 | 0.409 | 0.398 | - | 0.686 | 0.374 | 0.528 | 0.193 |
| SAEs | 0.510 | 0.381 | 0.529 | 0.185 | - | 0.411 | - | 0.816 | 0.624 | 0.444 | 0.585 |
-
PLA, placebo; ALE, alendronate; COL, clodronate; DEN, denosumab, ETI, eronate; IBA, ibandronate; PTH, parathyroid hormone; RAL, raloxifene; RIS, risendronate; STR, strontium ranelate; ZOL, zoledronic acid; NVF, new vertebral fractures; CVF, clinical vertebral fractures; AEs, adverse events; SAEs, serious adverse events
Discussion
This study compared the efficacy and safety of ten common prevention therapies for PMO treatment (ALE, COL, DEN, ETI, IBA, PTH, RAL, RIS, STR and ZOL). NVF was the primary endpoint; CVF, AEs and SAEs were the secondary endpoints. A NMA was performed to measure the efficacy and safety of these prevention therapies, in which 42 academic papers were involved, and provided head-to-head comparisons of different interventions.
The NMA results showed that all ten therapies were notably more effective than PLA in the prevention of NVF. ETI ranked first with a SUCRA value of 0.916, followed by PTH and ZOL. Furthermore, ZOL and DEN worked most efficiently in reducing the risk of CVF while the data reporting ETI in preventing CVF were not available in our study. In view of statistical insignificance, none of the therapies (PLA included) exhibited much difference in triggering AEs and SAEs. Moreover, the rank possibility of SUCRA of both NVF and CVF suggested that ZOL and PTH were recommended for clinical treatment because they ranked higher in the primary efficacy measurement. Even though ETI performed the best in NVF, its data about CVF were missing so we were unable to draw a conclusion about its efficacy.
Our results were in accordance with the mixed treatment comparison of bisphosphonate therapies undertaken by Jansen et al,64 which drew conclusions from seven RCTs and suggested that ZOL had a 98% probability of reducing the risk of NVF and was more effective than ALE, IBA and RIS. A meta-analysis performed by Cranney et al65 indicated that one to three years of ETI treatment increased bone density by 4.06% in the lumbar spine (95% CI 3.12 to 5.00), which was also consistent with our results.
According to the results, DEN worked well in preventing NVF and presented no statistical difference in AEs and SAEs. This was in accordance with previous studies.27,30 However, a meta-analysis consisting of approximately nine RCTs and 10 329 participants performed by Anastasilakis et al66 indicated that DEN caused a statistically insignificant reduction in fracture risk (OR = 0.74, 95% CI 0.33 to 1.64, p = 0.450) and an increased risk of SAEs (OR = 1.83, 95% CI 1.10 to 3.04, p = 0.020) and serious infections (OR = 4.45, 95% CI 1.15 to 17.14, p = 0.030). These results cast doubt on the safety of DEN. Nevertheless, due to a larger sample size and extensive comparisons of our studies, the confidence intervals presented in our study are relatively narrow, thus our results were more reliable. However, in a practical clinical environment, the patient’s adverse reactions should still be regularly monitored to improve medication safety.
One limitation of our study in the analysis of CVF and SAE, was the number of relevant studies being relatively small and some key comparisons were missing, meaning that most evidence came from indirect comparisons instead of direct comparisons. Consequently, the results of CVF and SAE should be interpreted with caution. Furthermore, the OR of RIS and ETI in preventing NVF contained a significant contradiction (direct: 0.34, indirect: 2.6) because all of the direct evidence comes from a single RCT performed by Fukunaga,19 which only involved 209 participants. In addition, the endpoint discontinuation should be taken into account. For example, ZOL is the only therapy administered to patients intravenously on a yearly basis, which means greater compliance of patients.67,68 This discrepancy led to an assumption that the significant performance of ZOL was partly attributed to the patient’s compliance. Despite the limitations above, our study fills the void in existing research, and most of our results fall in line with existing clinical studies and may have promising potential clinical implications.
In conclusion, this study suggests that PTH and ZOL have the highest probability of treatment efficacy. In view of the limitations above, we expect more clinical trials on PMO to be performed in order to continue closing the existing gaps in knowledge.
Supplementary material
Tables showing the search strategy and the efficacy and safety of agents for post-menopausal osteoporosis according to the network meta-analysis are available alongside this article online at www.bjr.boneandjoint.org.uk
Funding Statement
None declared.
*
G. Wang and L. Sui contributed equally to this study and are first co-authors.
Conflicts of Interest Statement
None declared.
References
1 Cummings SR , MeltonLJ. Epidemiology and outcomes of osteoporotic fractures. Lancet2002;359:1761-1767.CrossrefPubMed Google Scholar
2 Felsenberg D , SilmanAJ, LuntM, et al.. Incidence of vertebral fracture in europe: results from the European Prospective Osteoporosis Study (EPOS). J Bone Miner Res2002;17:716-724.CrossrefPubMed Google Scholar
3 Mauck KF , ClarkeBL. Diagnosis, screening, prevention, and treatment of osteoporosis. Mayo Clin Proc2006;81:662-672.CrossrefPubMed Google Scholar
4 Recker RR , KendlerD, RecknorCP, et al.. Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone2007;40:843-851.CrossrefPubMed Google Scholar
5 Manson JE , HsiaJ, JohnsonKC, et al.. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med2003;349:523-534.CrossrefPubMed Google Scholar
6 Watson J , WiseL, GreenJ. Prescribing of hormone therapy for menopause, tibolone, and bisphosphonates in women in the UK between 1991 and 2005. Eur J Clin Pharmacol2007;63:843-849.CrossrefPubMed Google Scholar
7 Paggiosi MA , PeelN, McCloskeyE, WalshJS, EastellR. Comparison of the effects of three oral bisphosphonate therapies on the peripheral skeleton in post-menopausal osteoporosis: the TRIO study. Osteoporos Int2014;25:2729-2741. Google Scholar
8 Ghinoi V , BrandiML. Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders. Expert Opin Pharmacother2002;3:1643-1656.CrossrefPubMed Google Scholar
9 Frediani B , CavalieriL, CremonesiG. Clodronic acid formulations available in Europe and their use in osteoporosis: a review. Clin Drug Investig2009;29:359-379.CrossrefPubMed Google Scholar
10 Fleisch HA . Bisphosphonates: preclinical aspects and use in osteoporosis. Ann Med1997;29:55-62.CrossrefPubMed Google Scholar
11 Black DM , SchwartzAV, EnsrudKE, et al.; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA2006;296:2927-2938. Google Scholar
12 Buehler J , ChappuisP, SaffarJL, TsouderosY, VigneryA. Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis). Bone2001;29:176-179.CrossrefPubMed Google Scholar
13 Cummings SR , San MartinJ, McClungMR, et al.. Denosumab for prevention of fractures in post-menopausal women with osteoporosis. N Engl J Med2009;361:756-765. Google Scholar
14 Ettinger B , BlackDM, MitlakBH, et al.. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA1999;282:637-645.CrossrefPubMed Google Scholar
15 Verhaar HJ , LemsWF. PTH analogues and osteoporotic fractures. Expert Opin Biol Ther2010;10:1387-1394.CrossrefPubMed Google Scholar
16 Henriksen K , AndersenJR, RiisBJ, et al.. Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis. Bone2013;53:160-166. Google Scholar
17 Wang C . Efficacy and Safety of Zoledronic Acid for Treatment of Post-menopausal Osteoporosis: A Meta-Analysis of Randomized Controlled Trials. Am J Ther2016 (Epub ahead of print) PMID: 26938765. Google Scholar
18 Serrano AJ , BegoñaL, AnituaE, CobosR, OriveG. Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis. Gynecol Endocrinol2013;29:1005-1014.CrossrefPubMed Google Scholar
19 Fukunaga M , KushidaK, KishimotoH, et al.. A comparison of the effect of risedronate and etidronate on lumbar bone mineral density in Japanese patients with osteoporosis: a randomized controlled trial. Osteoporos Int2002;13:971-979.CrossrefPubMed Google Scholar
20 Bucher HC , GuyattGH, GriffithLE, WalterSD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol1997;50:683-691.CrossrefPubMed Google Scholar
21 Mantel N , HaenszelW. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst1959;22:719-748.PubMed Google Scholar
22 DerSimonian R , LairdN. Meta-analysis in clinical trials revisited. Contemp Clin Trials2015;45:139-145.CrossrefPubMed Google Scholar
23 van de , SchootR, KaplanD, DenissenJ, et al.. A gentle introduction to bayesian analysis: applications to developmental research. Child Dev2014;85:842-860.CrossrefPubMed Google Scholar
24 Spiegelhalter DJ , FreedmanLS, ParmarMK. Applying Bayesian ideas in drug development and clinical trials. Stat Med1993;12:1501-1511.CrossrefPubMed Google Scholar
25 Jansen JP , FleurenceR, DevineB, et al.. Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 1. Value Health2011;14:417-428.CrossrefPubMed Google Scholar
26 Gnant M , PfeilerG, DubskyPC, et al.. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386:433-443.CrossrefPubMed Google Scholar
27 Black DM , ReidIR, CauleyJA, et al.. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res2015;30:934-944.CrossrefPubMed Google Scholar
28 Popp AW , BuffatH, CaveltiA, et al.. Cortical bone loss at the tibia in post-menopausal women with osteoporosis is associated with incident non-vertebral fractures: results of a randomized controlled ancillary study of HORIZON. Maturitas2014;77:287-293. Google Scholar
29 Thomas T , HorlaitS, RingeJD, et al.. Oral bisphosphonates reduce the risk of clinical fractures in glucocorticoid-induced osteoporosis in clinical practice. Osteoporos Int2013;24:263-269.CrossrefPubMed Google Scholar
30 Recknor C , CzerwinskiE, BoneHG, et al.. Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol2013;121:1291-1299.CrossrefPubMed Google Scholar
31 Bone HG , ChapurlatR, BrandiML, et al.. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab2013;98:4483-4492. Google Scholar
32 Reginster JY , FelsenbergD, BoonenS, et al.. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in post-menopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum2008;58:1687-1695. Google Scholar
33 Iwamoto J , SatoY, UzawaM, TakedaT, MatsumotoH. Comparison of effects of alendronate and raloxifene on lumbar bone mineral density, bone turnover, and lipid metabolism in elderly women with osteoporosis. Yonsei Med J2008;49:119-128.CrossrefPubMed Google Scholar
34 Ensrud KE , StockJL, Barrett-ConnorE, et al.. Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial. J Bone Miner Res2008;23:112-120.CrossrefPubMed Google Scholar
35 McCloskey EV , BenetonM, CharlesworthD, et al.. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res2007;22:135-141.CrossrefPubMed Google Scholar
36 Greenspan SL , BoneHG, EttingerMP, et al.. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med2007;146: 326-339.CrossrefPubMed Google Scholar
37 Black DM , DelmasPD, EastellR, et al.. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med2007;356:1809-1822.CrossrefPubMed Google Scholar
38 Palomba S , OrioFJr, MangusoF, et al.. Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease. Osteoporos Int2005;16:1141-1149.CrossrefPubMed Google Scholar
39 Hooper MJ , EbelingPR, RobertsAP, et al.. Risedronate prevents bone loss in early postmenopausal women: a prospective randomized, placebo-controlled trial. Climacteric2005;8:251-262.CrossrefPubMed Google Scholar
40 Chesnut CH , EttingerMP, MillerPD, et al.. Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE. Curr Med Res Opin2005;21:391-401.CrossrefPubMed Google Scholar
41 Meunier PJ , RouxC, SeemanE, et al.. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med2004;350:459-468.CrossrefPubMed Google Scholar
42 McCloskey E , SelbyP, DaviesM, et al.. Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res2004;19:728-736.CrossrefPubMed Google Scholar
43 Chesnut CH III , SkagA, ChristiansenC, et al.. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res2004;19:1241-1249.CrossrefPubMed Google Scholar
44 Morii H , OhashiY, TaketaniY, et al.. Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trial. Osteoporos Int2003;14:793-800.CrossrefPubMed Google Scholar
45 Shiota E , TsuchiyaK, YamaokaK, KawanoO. Effect of intermittent cyclical treatment with etidronate disodium (HEBP) and calcium plus alphacalcidol in postmenopausal osteoporosis. J Orthop Sc. 2001;6:133-136.CrossrefPubMed Google Scholar
46 Neer RM , ArnaudCD, ZanchettaJR, et al.. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med2001;344:1434-1441.CrossrefPubMed Google Scholar
47 Adachi JD , SaagKG, DelmasPD, et al.. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum2001;44:202-211.CrossrefPubMed Google Scholar
48 Wallach S , CohenS, ReidDM, et al.. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int2000;67:277-285.CrossrefPubMed Google Scholar
49 Reginster J , MinneHW, SorensenOH, et al.. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int2000;11:83-91.CrossrefPubMed Google Scholar
50 Fogelman I , RibotC, SmithR, et al.. Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. J Clin Endocrinol Metab2000;85:1895-1900.CrossrefPubMed Google Scholar
51 Harris ST , WattsNB, GenantHK, et al.. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA1999;282:1344-1352.CrossrefPubMed Google Scholar
52 Saag KG , EmkeyR, SchnitzerTJ, et al.. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med1998;339:292-299.CrossrefPubMed Google Scholar
53 Mortensen L , CharlesP, BekkerPJ, DigennaroJ, JohnstonCCJr. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. J Clin Endocrinol Metab1998;83:396-402.CrossrefPubMed Google Scholar
54 Lufkin EG , WhitakerMD, NickelsenT, et al.. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res1998;13:1747-1754.CrossrefPubMed Google Scholar
55 Cummings SR , BlackDM, ThompsonDE, et al.. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA1998;280:2077-2082.CrossrefPubMed Google Scholar
56 Montessori ML , ScheeleWH, NetelenbosJC, KerkhoffJF, BakkerK. The use of etidronate and calcium versus calcium alone in the treatment of postmenopausal osteopenia: results of three years of treatment. Osteoporos Int1997;7:52-58.CrossrefPubMed Google Scholar
57 Lyritis GP , TsakalakosN, PaspatiI, et al.. The effect of a modified etidronate cyclical regimen on postmenopausal osteoporosis: a four-year study. Clin Rheumatol1997;16:354-360.CrossrefPubMed Google Scholar
58 Clemmesen B , RavnP, ZegelsB, et al.. A 2-year phase II study with 1-year of follow-up of risedronate (NE-58095) in postmenopausal osteoporosis. Osteoporos Int1997;7:488-495.CrossrefPubMed Google Scholar
59 Bone HG , DownsRWJr, TucciJR, et al.. Dose-response relationships for alendronate treatment in osteoporotic elderly women. J Clin Endocrinol Metab1997;82:265-274.CrossrefPubMed Google Scholar
60 Adachi JD , BensenWG, BrownJ, et al.. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med1997;337:382-387.CrossrefPubMed Google Scholar
61 Black DM , CummingsSR, KarpfDB, et al.. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet1996;348:1535-1541.CrossrefPubMed Google Scholar
62 Liberman UA , WeissSR, BröllJ, et al.. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med1995;333:1437-1443.CrossrefPubMed Google Scholar
63 Storm T , ThamsborgG, SteinicheT, GenantHK, SørensenOH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med1990;322:1265-1271.CrossrefPubMed Google Scholar
64 Jansen JP , BergmanGJ, HuelsJ, OlsonM. Prevention of vertebral fractures in osteoporosis: mixed treatment comparison of bisphosphonate therapies. Curr Med Res Opin2009;25:1861-1868.CrossrefPubMed Google Scholar
65 Cranney A , GuyattG, KrolickiN, et al.. A meta-analysis of etidronate for the treatment of postmenopausal osteoporosis. Osteoporos Int2001;12:140-151.CrossrefPubMed Google Scholar
66 Anastasilakis AD , ToulisKA, GoulisDG, et al.. Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res2009;41:721-729. Google Scholar
67 Emkey R , KoltunW, BeusterienK, et al.. Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin2005;21:1895-1903.CrossrefPubMed Google Scholar
68 Ringe JD . Development of clinical utility of zoledronic acid and patient considerations in the treatment of osteoporosis. Patient Prefer Adherence2010;4:231-245.CrossrefPubMed Google Scholar
