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A. Abstract |
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 Top A. Abstract B. BackgroundC. MethodsD. ResultsE. DiscussionReferences |
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Data Source: We searched MEDLINE, EMBASE, Current Contents, and the Cochrane Controlled trials registry from 1980 to 1999, and we examined citations of relevant articles and proceedings of international meetings.
Study Selection: We included 11 trials that randomized women to alendronate or placebo and measured bone density for at least 1 yr.
Data Extraction: For each trial, three independent reviewers assessed the methodological quality and abstracted data.
Data Synthesis: The pooled relative risk (RR) for vertebral fractures in patients given 5 mg or more of alendronate was 0.52 [95% confidence interval (CI), 0.43–0.65]. The RR of nonvertebral fractures in patients given 10 mg or more of alendronate was 0.51 (95% CI 0.38–0.69), an appreciably greater effect than for the 5 mg dose. We found a similar reduction in RR across nonvertebral fracture types; in particular, RR reductions for fractures traditionally thought to be "osteoporotic," such as hip and forearm, were very similar to RR reductions for "nonosteoporotic" fractures. Individual studies showed similar results, reflected in the P values of the test of heterogeneity (P = 0.99 for vertebral and 0.88 for nonvertebral fractures).
Alendronate produced positive effects on the percentage change in bone density, which increased with both dose and time. After 3 yr of treatment with 10 mg of alendronate or more, the pooled estimate of the difference in percentage change between alendronate and placebo was 7.48% (95% CI 6.12–8.85) for the lumbar spine (2–3 yr), 5.60% (95% CI 4.80–6.39) for the hip (3–4 yr), 2.08% (95% CI 1.53–2.63) for the forearm (2–4 yr), and 2.73% (95% CI 2.27–3.20) for the total body (3 yr). Heterogeneity of the treatment effect of alendronate was not consistently explained by any of our a priori hypotheses; in particular, the effect was very similar in prevention and treatment studies.
The pooled RR for discontinuing medication due to adverse effects for 5 mg or greater of alendronate was 1.15 (95% CI 0.93–1.42). The pooled RR for discontinuing medication due to gastro-intestinal (GI) side effects for 5 mg or greater was 1.03 (0.81–1.30, P = 0.83), and the pooled RR for GI adverse effects with continuation of medication was 1.03 (0.98 to 1.07) P = 0.23.
Conclusions: Alendronate increases bone density in both early postmenopausal women and those with established osteoporosis while reducing the rate of vertebral fracture over 2–3 yr of treatment. Reductions in nonvertebral fractures are evident among postmenopausal women without prevalent fractures and have bone mineral density (BMD) levels below the World Health Organization threshold for osteoporosis. The impact on fractures appears consistent across all fracture types, casting doubt on traditional distinctions between osteoporotic and nonosteoporotic fractures.
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B. Background |
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TopA. AbstractB. BackgroundC. MethodsD. ResultsE. DiscussionReferences |
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C. Methods |
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TopA. AbstractB. BackgroundC. MethodsD. ResultsE. DiscussionReferences |
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1. Inclusion criteria.
Trials satisfied the following inclusion criteria: 1) randomized placebo-controlled trials (RCTs) comparing postmenopausal women receiving alendronate to those not receiving alendronate with follow-up of at least 1 yr; and 2) fracture incidence, or BMD data (including percentage change from baseline and a measure of variance) available. We made no restriction by country in which the trial occurred, nor did we limit the language to English. Eleven trials total met our inclusion criteria (1, 3, 6, 7, 8, 9, 10, 11, 12, 15, 14).
2. Study search and selection.
To identify relevant studies of alendronate therapy, we used the search strategy outlined in Section I and used the following key and text words: bisphosphonates, diphosphonates, osteoporosis, postmenopausal, and alendronate (15). We reviewed citations of relevant articles and conference proceedings. Two reviewers (A.C., V.R.) examined each title generated from the search and identified potentially eligible articles for which we obtained the abstracts. For abstracts consistent with study eligibility, we obtained the full article text.
3. Reproducibility.
Three reviewers judged study eligibility, assessed the methodological quality, and abstracted the data. We achieved a high level of chance corrected agreement in our rating of methodological quality for blinding (
1.0) and moderate agreement for loss to follow-up ( 0.6).
4. Outcomes and explanations for variability in alendronate effect across studies.
We examined the effect of alendronate on vertebral and nonvertebral fractures, bone density of the total body, lumbar spine, hip, and forearm, as well as adverse effects of the drug as manifested in patients unable to continue study medication. We developed, for fractures and bone density, a priori hypotheses that might explain heterogeneity of study results as outlined in Section I. Specifically, we compared groups according to 1) prevention vs. treatment; 2) concurrent treatments including total calcium intake (1250 mg of total calcium vs. <1250 mg); 3) vitamin D supplementation; 4) for nonvertebral fractures, sites in which fractures are strongly associated with low bone density and those not as strongly associated; and 5) individual components of the quality assessment, including concealed randomization, blinding, loss to follow-up, and intention-to-treat analysis. Section I includes a full description of the methodology used to separate prevention from treatment studies. To further evaluate heterogeneity of the severity of osteoporosis in women with BMD 2 SD values below the mean, we grouped trials with a prevalent vertebral fracture rate of greater than 10% at study inclusion (1, 3, 8, 12, 13), in comparison to those without fractures or prevalence below 10% (6, 7, 9, 10, 14). We chose the 10% cut because there was a cluster of studies just less than 10%, and a number of studies with fracture rates much greater than 10%. We also evaluated whether the treatment effect varied depending on baseline total calcium intake (cut point of 1250 mg) and presence of vitamin D supplementation.
5. Data collection.
Reviewers abstracted data regarding study design, patient characteristics, treatment duration, dosage, mean change, and SD values for bone density, and number of fractures, both vertebral and nonvertebral. We did not include data from the calcitonin treatment arm of Adami et al. (9) or the hormone replacement arm of the Hosking et al. (7) trial. We sought data missing from the original reports through correspondence with the primary investigators and with the company, Merck, that sponsored the trials. Merck provided us with the clinical study reports for all of the published trials included in this meta-analysis (1, 3, 6, 7, 8, 9, 10). For the trials not yet published at the time we collected data, we were able to obtain the clinical studies reports from Merck for the Clinical Fracture Arm of the Fracture Intervention Trial (FIT) (14), the draft manuscript of two trials (Refs. 11 and 12 ; both have since been published), and the data from the most recently completed RCT (13).
6. Analysis.
When we found duplicate reports of the same study in preliminary abstracts and articles (16, 17, 18), we analyzed data from the most complete data set (1, 9). A random effects model provided the strategy for final estimates of all treatment effects, whether for fractures, bone density, or toxicity (19). We only used data on one fracture per person in the analysis.
We conducted separate analyses using regression models for each bone density site (lumbar spine, combined hip, forearm, and total body) using the difference between the change in bone density for each dose group and the change in the placebo arm.
Across both fractures and bone density, the dominant parsimonious models generally allowed combining doses of 1 and 2.5 mg, almost invariably allowed combining the results from 10-, 20-, and 40-mg doses, and sometimes allowed combining the 5-mg dose with doses of 10–40 mg. Because the effect was smallest with doses of 1–2.5 mg, and because clinicians are not using doses lower than 5 mg, we present data only from arms using doses of 5–40 mg. Although clinicians are not using doses of 20–40 mg, in all but one instance we found their effect is similar to 10 mg, and including these trials allows a more precise estimate of the treatment effect associated with doses of 10–40 mg.
With regard to the duration of therapy, the dominant parsimonious model for bone density kept all years separate. In the one exception, we found we could combine yr 2 and 3 for total body bone density. Because clinicians should appropriately offer alendronate therapy for at least 2 yr, we present only data from two or more years of follow-up. For the bone density analysis, if there was statistically significant heterogeneity between studies (P < 0.05), we divided the studies into two groups according to a priori hypotheses and tested whether the effect sizes differed in the two groups of studies (20).
For each fracture analysis, we calculated a RR and tested for heterogeneity using a 
2 procedure (19). The same analytic strategy was used to deal with the proportion of patients who discontinued medication because of adverse effects.
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D. Results |
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TopA. AbstractB. BackgroundC. MethodsD. ResultsE. DiscussionReferences |
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). Of these 19, we excluded 8 for the following reasons: duplicate report or earlier report of another study (16, 17, 18), lack of a control group (21), duration less than 1 yr (22, 23, 24), and outcomes limited to histomorphometric data (25).
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presents the characteristics of the 11 trials that met our eligibility criteria. The trials included a total of 12,855 women, of whom 5,561 received placebo. Two trials dealt with prevention (6, 7), and the other nine trials involved women whose densitometry showed low bone density (1, 3, 8, 9, 10, 11, 12, 13, 14). Of the nine trials in women with low bone density, six included women with a prevalence of vertebral fractures at the beginning of the study of over 10% (Table 1). The Fracture Intervention Trial, which was the largest treatment trial, used a dose of 5 mg for the initial 2 yr and then switched to a 10-mg dose for the third year.
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2. Fractures.
For vertebral fractures, our analysis failed to reject pooling across the entire range of doses from 5 to 40 mg. The pooled estimate of the RR of vertebral fractures with alendronate from 8 trials randomizing patients to a dose of 5 mg of alendronate or greater (1, 3, 6, 7, 8, 9, 10, 14) showed a RR of 0.52 (95% CI 0.43–0.65), which was consistent across trials (heterogeneity P value 0.99; Fig. 2). Thus, it is not surprising that, of our five a priori hypotheses, none showed statistically significant differences between subgroups. In particular, the point estimates for the reduction in fracture risk was similar for the prevention trials (RR of 0.45, 95% CI 0.06–3.15) and treatment trials (RR of 0.53, 95% CI 0.43–0.65. P value on difference between estimates 0.87).
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presents the RR for fracture with alendronate in the groupings of the nonvertebral fractures we examined. We found statistically significantly smaller effect sizes for 5 mg than for 10–40 mg of alendronate in every fracture category. At doses in the 10- to 40-mg range, the effect on each fracture category is similar, with the RRs varying from 0.45 to 0.57. The results across studies are quite similar, reflected in both the heterogeneity P values in Table 2 and Fig. 3, which presents the results of doses of 10 mg or more for individual studies for total nonvertebral fractures. Once again, the nonsignificant reduction in risk of all nonvertebral fractures in the one prevention trial (RR of 0.79, 95% CI 0.28–2.24) was not clearly different from the five treatment trials (RR 0.49, 95% CI 0.36–0.67, P value on difference between estimates 0.40). These results did not change for the 10- to 40-mg dose if we used a femoral neck T-score cut point of -2.5, instead of -2.0, to classify the trials into prevention and treatment. When we pooled across studies using 5 mg and greater for outcome of hip fracture, the pooled RR is 0.63 (0.43,0.92). The point estimate lies between the 5 mg and 10 to 40 mg estimates, and the 95% CI excludes no effect.
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presents the results of the pooled estimates of effect of alendronate on bone density across the four sites. All sites had a significant positive response to treatment with alendronate (P < 0.01), but we found consistently larger effects with the higher doses of alendronate than with the 5-mg dose, and larger effects as duration of follow-up increased in the lumbar spine (Fig. 4) and forearm and hip sites. For combined forearm, we found no statistically significant heterogeneity, whereas for total body, lumbar spine, and hip there were differences in the treatment effect between trials in some subgroups (Table 3). Even when statistically significant heterogeneity existed, all studies still demonstrated appreciable differences in favor of alendronate.
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4. Publication bias.
Funnel plots provided no suggestion of publication bias for any of bone density or vertebral or nonvertebral fractures.
5. Adverse effects.
Our pooled estimate of the RR of discontinuing medication as a result of adverse effects from 9 trials using 5 mg of alendronate or more of 1.15 (95% CI 0.93–1.42) was very consistent across trials (heterogeneity P value 0.82). The pooled RR for discontinuing medication to GI side effects for 5 mg or greater from 7 trials was 1.03 (0.81–1.30, heterogeneity P = 0.83). The pooled RR for GI adverse effects from 10 trials with continuation of medication was 1.03 (0.98–1.07, heterogeneity P = 0.23).
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E. Discussion |
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TopA. AbstractB. BackgroundC. MethodsD. ResultsE. DiscussionReferences |
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Our statistical power to detect heterogeneity was extremely limited for some tests due to the low number of fractures in some categories. Of particular concern in this regard is our exploration of differences in effect between treatment and prevention trials. We found very similar effects on bone density in prevention and treatment trials and a similar RR of fracture in trials with varying baseline levels of bone density. Although our bone density results are relatively robust, the number of fractures in the prevention trials was very small and the CIs very wide. As a result, our analyses have very little power to detect differences in relative risk reduction of fracture with alendronate and control across prevention and treatment groups.
Our lack of access to individual patient data limited our power to explore this issue further. An analysis from one study (26) suggested that alendronate’s effect in reducing nonvertebral fractures is greater in patients who begin treatment with lower bone density. Similar findings have been noted in clinical trials with other bisphosphonates, including etidronate and risedronate (27, 28). In conclusion, the existing data have not resolved the question of whether important differences in risk reduction across groups of patients with varying degrees of osteoporosis exist. The impact of alendronate on the relative risk of nonvertebral fracture in populations without major decrease in bone density merits further investigation.
Turning to the question of whether our estimates of alendronate effect apply to all nonvertebral fractures, most investigators have intuitively assumed that antiosteoporotic drugs will reduce fracture rates that are associated with low bone density and minimal trauma. In keeping with this line of thinking, we made a priori hypotheses that we might find larger alendronate-induced reduction in the RR of fractures of the hip, spine, forearm, or other fractures previously associated with reduced bone density. However, we found that the RR reduction with alendronate doses of 10 mg or greater was extremely consistent—for wrist, hip, vertebral, and indeed for fractures traditionally considered "nonosteoporotic." To us, this provides strong evidence that our pooled estimate of RR (0.51) and the associated CI (0.38–0.69) applies to all nonvertebral fractures. Our failure to find an appreciable gradient across osteoporotic and nonosteoporotic fractures challenges prior assumptions in this area.
With respect to bone density, we found that doses of alendronate 10 mg or greater had larger effects on bone density than smaller doses. Alendronate at doses of 10–40 mg increased bone density substantially, with larger increments in sites with a relatively high proportion of cancellous bone. Although we observed larger effects as time passed, the incremental gain of treatment over control in bone density decreased progressively with each succeeding year.
In analyses of differences in percentage change in bone mineral density, even where there was substantial inconsistency with statistically significant heterogeneity, alendronate increased bone density in all trials. When significant heterogeneity was present, we failed to uncover a compelling explanation.
Regarding the long-term impact of alendronate on fractures, we do not feel confident extrapolating beyond the duration of follow-up of the trials in our review. Data from longer term trials that are ongoing will help establish whether the effect on vertebral fractures is maintained, increased, or diminished.
Merck’s collaboration greatly facilitated our obtaining complete data from all published and unpublished studies. As a result, we were largely successful in obtaining relevant data. Our success in obtaining near-complete data constitutes a strength of this systematic review.
In general, the trials were methodologically strong. Their major methodological limitation was the loss to follow-up (Table 1). However, two trials achieved loss to follow-up of less than 5% (3, 14). It is reassuring that the proportion of patients lost to follow-up did not appear to influence the magnitude of the treatment effect in any analyses. Another limitation is the length of follow-up, 4 yr or less in all studies to date.
The RR for discontinuing alendronate due to adverse effects was 1.15 (95% CI 0.93–1.42). One of the limitations of evaluating data on adverse effects from summary meta-analyses is that participants in RCTs tend to be healthier with fewer co-morbid diseases, and the results may not be generalizable to clinical practice. For example, in a number of the alendronate trials, women were excluded if they had a history of peptic ulcer disease, or esophageal disease within a year of study entry. In addition, RCTs are underpowered for rare effects, and meta-analyses of RCTs generally cannot provide definitive information about drug toxicity.
Table 4 presents the absolute reductions in fracture risk we could anticipate over a 2-yr period in women with varying fracture risk receiving a dose of alendronate of 5 mg or greater for vertebral fractures. To make these calculations, we have estimated baseline risk from pooled estimates from the prevention trials of patients with normal bone density (low risk) and from the treatment trials that enrolled women with low BMD (high risk). Table 4 also presents the absolute reduction in fracture risk for high risk women receiving 10 mg or greater for nonvertebral fractures. We have not included the absolute reduction for the low risk population because, as we have noted previously, the magnitude of the RR reduction in nonvertebral fractures with alendronate in low-risk populations remains open to question.
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Acknowledgments |
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Footnotes |
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References |
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TopA. AbstractB. BackgroundC. MethodsD. ResultsE. DiscussionReferences |
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