The relative efficacy of nine osteoporosis medications for reducing the rate of fractures in post-menopausal women

Osteoporosis defined by low Bone Mineral Density (BMD) (i.e., 2.5 standard deviations below peak gender specific BMD), is a progressive disease with high prevalence affecting 1 in 3 women and 1 in 8 men by the time they reach 90 years of age [1]. The major concern with low BMD is the high risk of fractures to non-vertebral bones such as the wrist or to the hip. A hip fracture may require extended hospital stay, surgical repair and rehabilitation therapy, and is associated with increased risk of death [2]. In addition, osteoporosis can lead to vertebral fractures which are identified by clinical assessment through decreased patient height (i.e., stooped posture) or with compressed spinal vertebra that can be radiologically assessed [3].

To reduce the risk of fractures due to osteoporosis, drugs have been introduced to reduce the rate of bone loss and to increase the strength of the bones. The first bisphosphonate available in Canada was etidronate in 1995 followed by alendronate in 1998. In 2005, alendronate became generic, which introduced a large increase in the uptake of these drugs. In Canada in 2010 about 9% of the population age 50 years and over were receiving an osteoporosis drug. These drugs include the bisphosphonates (alendronate, etidronate, risedronate or ibandronate), Selective Estrogen Receptor Modulators (raloxifene) and anabolic agents (teriparatide). All of these have shown to be effective in reducing the rate of fractures relative to placebo [4]. Recent additions to pharmacotherapy for osteoporosis include denosumab, strontium and zoledronic acid. Accordingly, it would be clinically important to know an estimate of the relative treatment efficacy or ranking of the most efficacious drugs. A major gap in the evidence to identify the most efficacious drugs is the lack of randomized active-controlled trials, i.e., direct treatment comparison (DTC) evidence [4].

DTC evidence for osteoporosis is absent because such later stage III trials are more complex, expensive, and require larger sample sizes than earlier phase II randomized placebo-controlled trials (RPCT) [5]. Meanwhile, osteoporosis drugs have been approved for use or listed under reimbursement formularies based on RPCT evidence, even though there are skeptics on the benefits of RPCTs for estimating relative efficacy compared to currently available drugs and that RPCTs are unethical. In a recent New England Journal of Medicine debate, Stein [6] argued that RPCTs are unethical because of the withholding of proven therapies in the placebo allocation, while Rosen [7] argued that the therapies are only proven in high risk patients (prior fracture, BMD < -3, or higher fracture risk assessment) and the inclusion criteria that possess true equipoise should only include individuals who are at low risk or are non-responsive to mild therapies. However in Canada the Tri-Council Policy Statement on the Ethical Conduct for Research Involving Humans suggest that RPCTs are acceptable to establish existence of effect and adverse events of drugs with new pharmacological mechanisms [8]. In the absence of DTC evidence, indirect treatment comparisons (ITC) might be a promising technique that allows the synthesis of available RPCT evidence to make a suggestion on the effect of DTC [9]. The theoretical foundations of the ITC method were provided in 1997 by Bucher [10] for the pair wise division of odds ratios to produce a common odds ratio thereafter referred to as the Bucher Method (i.e., for 2 drugs A and C and placebo B, the odds ratio of A/B divided by odds ratio C/B produces an odds ratio of A/C). While DTC is the highest level of clinical evidence, there exists the rationale to use ITC analysis where DTC is absent and not likely to be forthcoming [10]. Even if DTC evidence was available, ITC evidence based on other trials may be useful because of differences in patient characteristics and study characteristics such as length of follow-up [11].

In the absence of DTC evidence for osteoporosis drugs, two ITC analyses have been conducted to assess the relative efficacy at reducing the rates of fractures in post-menopausal women [12, 13]. The first using a Bayesian analysis that looked at seven studies including four drugs zoledronic acid (1 study), alendronate (3 studies), ibandronate (1 study) and risedronate (2 studies). this indicated that zoledronic acid had the highest efficacy in preventing vertebral fractures [12]. The second and more comprehensive analysis included eight RPCTs which was an update involving the above four medications adding etidronate (1 study). Of the five medications analyzed zoledronic acid had the highest efficacy in preventing vertebral and hip fractures while risedronate had the highest efficacy in reducing non-vertebral non-hip fractures [13].

We believe we can build on this pioneering work. First, nine drugs are currently available in Canada, European or the United States for use with osteoporosis. The nine drugs include the above five (zoledronic acid, alendronate, ibandronate, and risedronate) in the recent ITC analysis plus four more drugs that were not previously included (denosumab, raloxifene, strontium, and teriparatide). In addition, there are key differences in patient characteristics across the studies such as age, BMD, and fracture history. Further adjustment for these factors might affect estimates of the relative efficacy between treatments.

The purpose of this paper is to build on the previous estimation of relative efficacy between osteoporosis drugs for the prevention of fractures. First, we update the literature on osteoporosis drugs to include recent additions in pharmacotherapy and recent RPCTs by conducting a multiple database systematic literature review. Second, we estimate the relative efficacy of reducing fractures of each drug versus placebo and between the drugs with Bayesian ITC analysis. Third, we conduct the ITC analysis using Bucher's method, a classical analysis approach. Finally, we estimated the relative efficacy after adjustment for baseline patient characteristics.

Based on the literature review, 30 RPCTs that investigated the effect of drugs on the rate of fractures were identified. The results of the screening process are provided in the PRISMA diagram [25] in Figure 1 and the descriptions of the included studies are presented in Table 1. For the 9 drugs, 6 studies were for alendronate [26‐31], 1 study for denosumab [32], 8 studies for etidronate [33‐40], 4 studies for ibandronate [41‐44], 1 study for raloxifene [45], 6 studies for risedronate [46‐51], 2 studies for strontium [52, 53], 1 for teriparatide [54], and 1 for zoledronic Acid [55]. The participants in the studies included 59,209 patients. The participants had a mean age ranging in studies between 52 and 72 years of age, years since menopause ranged from 2.7 to 31.9 years, and the study durations were from 1 to 4 years. Baseline BMD in the hip ranged from 0.28 to 1.08 and the percentage of participants that had previous vertebral fractures were from 0% to 100%.

The objective was to update the literature on the relative efficacy of different osteoporosis medications to prevent four types of osteoporosis-related fractures. Based on the combination of effect size and probability of being most efficacious, teriparatide zoledronic acid and denosumab are consistently ranked highest for reducing non-vertebral and vertebral fractures, the two most common types of fractures

Etidronate is also ranked high on probability of being most efficacious but there are reservations with this result. First, etidronate does not have a statistically significant odds ratio versus placebo for non-vertebral fracture, but was ranked highest for being efficacious. The higher ranking may be due to a wide confidence interval that covers a lower region of odds ratio creating a favourable relative result over that region of low odds ratio. This suggests a limitation with this analysis where a requirement may be that the odds ratio for different drugs should have similar widths. A second caution with the results for etidronate is that the trials were small resulting in small effect sizes and the trials were conducted prior to the year 2000. This suggests that there is a lack of current strong evidence for the efficacy of etidronate versus placebo. As a result of these two limitations, this analysis suggests that etidronate should not be considered among the most efficacious drugs based on current evidence.

In addition, the number needed to treat analysis that treating as few as 10 patients with teriparatide, zoledronic acid or denosumab will produce 1 less fracture than if the patients were on other drugs.

This work updates the most recent study for ITC analysis in osteoporosis medications which looked at vertebral, hip and nonvertebral nonhip fractures [13] for five drugs, zoledronic acid, alendronate, ibandronate, risedronate and etidronate. Based on that analysis zoledronic acid had a 0.79 probability of being the most efficacious for vertebral fractures. In our analysis, teriparatide (0.40) and etidronate (0.40) had the highest probability of being the most efficacious. In our analysis, we included more studies for etidronate, alendronate, and risedronate in addition to adding denosumab, raloxifene, strontium and teriparatide. Similarly, the earlier work reported that zoledronic acid had the highest probability of preventing hip fractures, while our analysis indicates the most efficacious drugs are teriparatide (0.44), and that zoledronic acid (0.11), etidronate (0.19), denosumab (0.12) and alendronate (0.10) could be the most efficacious treatment. One key difference between inclusions of different studies was that we analyzed wrist fractures specifically while the earlier work reported on nonvertebral nonhip fractures [13]. We report that risedronate does have a high probability of being most efficacious similar to earlier work but we estimated that teriparatide has the highest probability of preventing wrist fractures (0.44).

The other objective of this analysis was to compare the results across two statistical methods. The first method was based on Bayesian ITC analysis in WinBUGS, and the second method was the results from classical Bucher analysis with ITC specific software. The estimates differed only by the second decimal place when the results were statically significant. However, there are key differences in the interpretation of the results. Based on the classical analysis we generated confidence intervals around the odds ratio and provided a test of association. In the Bayesian analysis, we generated a posterior distribution of the credible intervals for the true values of the odds ratio. In this analysis these values are similar, indicating that the priors used in the analysis were uninformative.

The analysis is limited in that the results are based on ITC comparisons. However, a recent review of the results of DTC and ITC analysis, described that out of 44 meta-analysis that were available with studies for meta-analysis by ITC and studies for meta-analysis by DTC, the DTC was similar in all but 3 cases to the ITC estimates for the same drugs and outcomes [9]. Of the 3 cases where the results were statistically different, 2 cases had the relative clinical benefit in the same direction while the third had differences in dosage regime in the studies. This result was also reported by Bucher in 1997 [10] where the ITC results were similar in direction as the DTC estimates. In addition, Bucher and Song both reported that the magnitude of the ITC results was larger between comparators than DTC comparisons, and the level of significance between comparators was less in ITC than DTC. In our ITC analysis, non-significant differences were estimated between drugs but the true effect between drugs may be even smaller.

The other assessment of strength of evidence in the indirect comparisons beyond looking at different classical versus Bayesian analysis was to look at heterogeneity within drugs and across drugs. The heterogeneity between comparators and heterogeneity within one comparator was small, with the exception of alendronate for wrist fractures. This heterogeneity was explained by two studies [28, 29] for wrist fractures. These studies did not contribute to heterogeneity in the meta-analysis of vertebral fractures and non-vertebral fractures. However, these two studies included the one study [28] that was the longest study with duration of 4 years with a low risk patients and the largest study for alendronate, while the other study [29] was small single centre study with duration of 4 years with low risk patients and the largest study.

The interpretation of the heterogeneity, although not a major feature in this analysis, is an important factor for ITC analysis. Increased heterogeneity can be caused by differences in inclusion criteria or study design such as length of follow-up. These are also important factors for consideration for analysis of DTC studies [20]. Three studies assessed the effect of patient characteristics to explain the level of heterogeneity in ITC analysis. In 2 studies [56, 57] no baseline variables were significant while in the other study [58] the year of the study and baseline risk affected heterogeneity. Both of these factors may have also affected heterogeneity if the studies were randomized with an active comparator. In our analysis, we may not have enough power to detect the impact of baseline characteristics because of a low number of studies for each drug [22]. In addition, because of the high heterogeneity in the estimates of odds ratios for wrist fractures, the evidence for wrist fractures should be considered weak.

ITC is becoming a useful tool in the absence of DTC comparisons and increasing transparency of ITC analysis builds confidence for the evidence. In a review of 88 ITC analyses, many of the studies could have increased the believability of their results [9] but the missed elements would also concern DTC analysis. These include incomplete searches or not assessing heterogeneity within a comparator. In 40/88 analysis there was no specific searches for active comparison studies to allow the comparison to the ITC evidence. For osteoporosis, this search was conducted and we found no published meta-analysis of DTC evidence. In the future stronger evidence may come from head-to-head studies but this is unlikely, because based on this analysis differences between comparators are not significant and studies would require very large sample sizes. Alternatively, the treatment analysis could come for pooling patient level data to compare the effects directly but this is unlikely due to propriety, and this analysis would diminish the benefits of randomization.

In light of the lack of DTC evidence, the ITC analysis of RPCTs may be the strongest evidence that will be available that answers the important clinical question of determining the most efficacious treatment for preventing fractures. In this analysis, teriparatide, zoledronic acid and denosumab have the highest probabilities of being most efficacious for non-vertebral and vertebral fractures, and having the greatest effect sizes. The estimates from indirect comparisons were robust to differences in methodology.