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Context: Osteoporosis and osteopenia are associated with increased fracture incidence.
Objective: The aim of this study was to determine the comparative effectiveness of different
pharmacological agents in reducing the risk of fragility fractures.
Study Selection: Eligible studies were randomized controlled trials enrolling individuals at risk of
developing fragility fractures and evaluating the efficacy of bisphosphonates, teriparatide, selec-
tive estrogen receptor modulators, denosumab, or calcium and vitamin D.
Data Extraction: Reviewers working independently and in duplicate determined study eligibility
and collected descriptive, methodological quality, and outcome data.
Data Synthesis: This network meta-analysis included 116 trials (139,647 patients; median age, 64
yr; 86% females and 88% Caucasians; median follow-up, 24 months). Trials were at low to mod-
erate risk of bias. Teriparatide had the highest risk reduction of fractures (odds ratios, 0.42, 0.30,
and 0.50 for hip, vertebral, and nonvertebral fractures, respectively) and the highest probability of
being ranked first for efficacy (probabilities of 42, 49, and 79% for hip, vertebral, and nonvertebral
fractures, respectively). However, differences to denosumab, zoledronate, risedronate, ibandro-
nate, and alendronate were not statistically significant. Raloxifene and bazedoxifene were likely
less effective, although these data were limited. Calcium and vitamin D were ineffective given
separately but reduced the risk of hip fractures if given in combination (odds ratio, 0.81; 95%
confidence interval, 0.68 – 0.96).
Conclusions: Teriparatide, bisphosphonates, and denosumab are most effective in reducing the
risk of fragility fractures. Differences in efficacy across drugs are small; therefore, patients and
clinicians need to consider their associated harms and costs. (J Clin Endocrinol Metab 97: 1871–1880,
2012)
ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: CI, Confidence interval; OR, odds ratio; SERM, selective estrogen receptor
Printed in U.S.A. modulator.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2011-3060 Received November 7, 2011. Accepted March 7, 2012.
First Published Online March 30, 2012
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1872 Murad et al. Drug Treatments to Prevent Fragility Fractures J Clin Endocrinol Metab, June 2012, 97(6):1871–1880
The protocol for this systematic review was established a priori Study selection
and approved by a task force formed by The Endocrine Society. Pairs of reviewers independently evaluated eligibility of can-
didate titles and abstracts. When at least one reviewer deter-
Eligibility criteria mined an article was potentially eligible, the full text version was
Trials eligible for inclusion in this review were: 1) randomized retrieved and pairs of reviewers assessed its eligibility. We used
controlled trials; 2) trials that enrolled patients with established standardized and piloted electronic forms using an online refer-
or at risk for osteoporosis; 3) trials that compared one or more ence management system (Distiller SR, Ottawa, Canada).
of the interventions of interest to each other or to placebo; and
4) trials that measured the outcomes of interest, i.e. fragility
Data extraction and quality assessment
fractures (vertebral, hip, and nonvertebral fractures).
The interventions of interest were: bisphosphonates (alen- Pairs of reviewers extracted data in duplicate, with disagree-
dronate, risedronate, zoledronate, and ibandronate), PTH 1-34 ments resolved by discussion and consensus. Study selection and
(teriparatide), SERM such as raloxifene or bazedoxifene, deno- data extraction (focusing on judgment of quality indicators) had
sumab, and calcium and vitamin D. The task force decided to not adequate chance-adjusted interreviewer agreement above 0.80.
include calcitonin because its fracture-preventing effect is gen- We evaluated the quality of trials using elements from the Co-
erally considered to be very weak (5) and supported by low- chrane risk of bias tool (18) focusing on allocation concealment,
quality evidence (3, 6), and because it is not commonly used for blinding (patients, investigators, data collectors, and outcome
modern long-term preventive therapy (7, 8). Pamidronate, assessors), outcome assessment, loss to follow-up (attrition), and
etidronate, strontium and lasofoxifene were also not included in the extent of prognostic balance of study arms at the start of the
this review because they are not approved by the Food and Drug study. The quality of evidence was judged using the GRADE
Administration for the treatment of osteoporosis, the main focus framework (Grading of Recommendations, Assessment, Devel-
of the accompanying guidelines (9). opment, and Evaluation) (19).
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J Clin Endocrinol Metab, June 2012, 97(6):1871–1880 jcem.endojournals.org 1873
Results
The process of selecting the trials is de-
scribed in Fig. 1. A total of 116 studies
provided data for meta-analysis. These
studies included 139,647 patients with a
median age of 64 yr; 86% were females
and 88% Caucasians. The median length
of follow-up was 24 months. The de-
scription of the included trials is in Sup-
plemental Table 1. The quality indicators
of these studies are described in Supple-
mental Table 2.
Meta-analysis
The available direct comparisons
FIG. 1. Study selection process. (i.e. two interventions are being com-
pared against each other in a random-
Statistical analysis ized controlled trial setting) are graph-
Direct head-to-head comparisons were conducted using a ically depicted in network graphs in Supplemental Figs.
random effects model to estimate pooled odds ratios (OR) and
1–3, including the number of trials, participants, and
95% confidence intervals (CI) incorporating within- and be-
tween-study heterogeneity (20). We assessed publication bias by events (fractures). The estimates obtained from direct
examining funnel plots symmetry and by conducting Egger’s comparisons are presented as OR and 95% CI and sum-
regression test (21). Heterogeneity was assessed using the I2 sta- marized in Supplemental Tables 3–5. There was no sig-
tistic (22), which represents the proportion of heterogeneity that
is not due to chance (but rather due to real differences across
nificant association between the duration of the interven-
studies’ populations and interventions). I2 values over 50% in- tion and the effect size (log OR) for all the included agents
dicate substantial heterogeneity. Direct comparisons were per- (P value for the slope of feasible meta-regression analyses
formed using the Comprehensive Meta-analysis version 2 soft- ⬎0.05). Vitamin and calcium given separately did not re-
ware package (Biostat Inc., Englewood, NJ).
To incorporate indirect comparisons, we conducted random- duce the risk of any fracture.
effects network meta-analyses using Markov chain Monte Carlo
methods in WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge, Hip fractures
UK) following methods described by Lu and Ades (23). We modeled Network meta-analysis combining direct and indirect es-
the comparative effectiveness of any two treatments as a function of
timates demonstrates that teriparatide had the highest prob-
each treatment relative to the reference treatment (i.e. placebo in this
study). This approach assumes “consistency” of treatment effects ability (42%) of being ranked as most effective and had the
across all included trials—that is, the direct and indirect estimates of highest reduction in the risk of hip fracture (OR, 0.42). Re-
effect for each pair-wise comparison do not disagree beyond sults are summarized in Table 1. Compared with placebo,
chance. We evaluated inconsistency by comparing the estimates
there was significant reduction in the risk of hip fracture with
from the direct comparisons and those from the indirect compari-
sons for the magnitude and direction of the point estimates and the alendronate, zoledronate, risedronate, denosumab, and the
extent of overlap of CI. We estimated the posterior distribution of combination of calcium and vitamin D. Results are summa-
all parameters using noninformative (i.e. vague, flat) priors to limit rized in Fig. 2.
inference to data derived from the trials at hand (i.e. we made no
assumptions about the efficacy of these drugs from data external to
the 116 trials included in this systematic review). We updated three Vertebral fractures
Markov chain Monte Carlo chains with 60,000 simulated draws Network meta-analysis combining direct and indirect
after a burn in of 30,000 iterations using the same seed number estimates demonstrates that teriparatide had the highest
(seed ⫽ 1000) for all chains. We reported the pair-wise OR and
probability (49%) of being ranked as most effective and
95% credible interval and adjusted for multiple arm trials.
We estimated the probability that each drug was the most had the highest reduction in the risk of vertebral fracture
efficacious regimen by calculating the OR for each drug com- (OR, 0.30). Results are summarized in Table 2. Compared
pared with an arbitrary common comparison drug (which was with placebo, there was significant reduction in the risk of
placebo in most cases due to the minimal number of head-to-
vertebral fractures with teriparatide, denosumab, alen-
head trials), and counting the proportion of iterations of the
Markov chain in which each drug had the largest OR in reducing dronate, zoledronate, ibandronate, risedronate, and
fracture risk. raloxifene. Results are summarized in Fig. 2.
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1874 Murad et al. Drug Treatments to Prevent Fragility Fractures J Clin Endocrinol Metab, June 2012, 97(6):1871–1880
TABLE 1. Pair-wise OR (95% Bayesian credible interval) of the outcome of hip fracture (combining direct and
indirect estimates)
Treatment Placebo Teriparatidea Denosumaba Raloxifeneb Zoledronatea Risedronateb
Placebo
Teriparatidea 0.42 (0.10; 1.82)
Denosumaba 0.50 (0.27; 0.86) 1.17 (0.24; 5.54)
Raloxifeneb 0.87 (0.63; 1.22) 2.05 (0.47; 9.47) 1.76 (0.95; 3.41)
Zoledronatea 0.50 (0.34; 0.73) 1.18 (0.26; 5.30) 1.02 (0.54; 1.93) 0.57 (0.35; 0.93)
Risedronateb 0.48 (0.31; 0.66) 1.12 (0.25; 4.98) 0.96 (0.50; 1.78) 0.55 (0.31; 0.84) 0.96 (0.56; 1.49)
Ibandronatea 0.49 (0.21; 1.20) 1.11 (0.22; 6.42) 0.98 (0.36; 2.79) 0.55 (0.23; 1.42) 0.97 (0.39; 2.55) 1.02 (0.43; 2.66)
Alendronateb 0.45 (0.27; 0.68) 1.02 (0.24; 4.82) 0.90 (0.45; 1.78) 0.51 (0.29; 0.87) 0.90 (0.51; 1.51) 0.93 (0.54; 1.62)
Vitamin Dc 1.13 (0.94; 1.34) 2.67 (0.63; 11.97) 2.28 (1.28; 4.16) 1.30 (0.89; 1.86) 2.26 (1.50; 3.42) 2.35 (1.63; 3.76)
Vitamin D ⫹ 0.81 (0.68; 0.96) 1.92 (0.45; 8.42) 1.64 (0.97; 2.87) 0.94 (0.66; 1.31) 1.63 (1.16; 2.30) 1.69 (1.27; 2.54)
calciumc
Calciumc 1.14 (0.82; 1.59) 2.69 (0.63; 12.23) 2.33 (1.25; 4.40) 1.31 (0.83; 2.06) 2.29 (1.44; 3.66) 2.39 (1.56; 4.04)
OR ⬍1 favors the treatment in the row, OR ⬎1 favors the treatment in the column. P, Probability being ranked as first, second, and third most
effective. Total number of trials ⫽ 40. Total number of participants ⫽ 139,647. Total number of hip fractures ⫽ 2,567.
a
With vitamin D and calcium.
b
With or without vitamin D and calcium.
c
With or without placebo.
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J Clin Endocrinol Metab, June 2012, 97(6):1871–1880 jcem.endojournals.org 1875
TABLE 1. Continued
2.36 (0.92; 5.87) 2.56 (1.57; 4.34) 1.01 (0.72; 1.44) 1.40 (1.03; 1.95) 0.00 0.00 0.00
sistent and fairly large effect, minimal heterogeneity, and ties generated in the network meta-analysis are clearly as-
a sufficient number of trials). The evidence supporting the sociated with significant uncertainty.
efficacy of SERM such as raloxifene or bazedoxifene is of
low quality mainly due to imprecision [i.e. small number
Discussion
of trials and events (fractures)]. Evidence supporting com-
parative effectiveness across these therapeutic classes is We conducted a network meta-analysis of several phar-
low [due to imprecision and minimal direct evidence macological agents available for the prevention of fragility
(head-to-head comparisons)], and the ranking probabili- fractures. We found moderate- to high-quality evidence to
FIG. 2. Agents for the prevention of fragility fractures compared against placebo (combined direct and indirect estimates).
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1876 Murad et al. Drug Treatments to Prevent Fragility Fractures J Clin Endocrinol Metab, June 2012, 97(6):1871–1880
TABLE 2. Pair-wise OR (95% Bayesian credible interval) of the outcome of vertebral fracture (combining direct and
indirect estimates)
support the efficacy of teriparatide, denosumab, and bis- had the highest probability of being most effective. This
phosphonates compared with placebo, vitamin D, and cal- ranking procedure has several limitations, the most im-
cium; and very low-quality evidence to support the com- portant of which is that the ranking does not convey a
parisons among these three classes of drugs. The evidence sense of the treatment effect in absolute terms. In other
supporting the efficacy of SERM such as raloxifene or words, the ranking has limited value when patients and
bazedoxifene on fractures remains imprecise due to the clinicians are trying to consider the trade-offs of drugs and
small number of events. The combination of vitamin D balance the benefits and harms.
and calcium appears to be the least effective, and either A key aspect to consider is the known phenomenon of
intervention is not effective given alone. Bayesian analyses overestimation of treatment effect sizes with the first few
ranked the efficacy of drugs producing the “probability of trials of a novel agent, the Proteus phenomenon (46),
being ranked first,” which demonstrated that teriparatide which may be influencing the relative rankings presented
TABLE 3. Pair-wise OR (95% Bayesian credible interval) of the outcome of nonvertebral fracture (combining direct
and indirect estimates)
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J Clin Endocrinol Metab, June 2012, 97(6):1871–1880 jcem.endojournals.org 1877
TABLE 2. Continued
Vitamin D ⴙ
Ibandronatea Alendronateb Vitamin D calcium Calcium P (best) P (2nd best) P (3rd best)
0.00 0.00 0.00
0.49 0.27 0.15
0.27 0.32 0.24
0.00 0.01 0.02
0.21 0.31 0.29
0.01 0.04 0.14
0.00 0.01 0.02
0.81 (0.52; 1.38) 0.00 0.02 0.07
1.55 (0.81; 3.11) 1.91 (1.01; 3.53) 0.00 0.00 0.00
1.60 (1.14; 2.50) 1.99 (1.44; 2.74) 1.04 (0.60; 1.83) 0.00 0.00 0.00
1.14 (0.67; 2.01) 1.41 (0.89; 2.17) 0.74 (0.40; 1.34) 0.71 (0.46; 1.05) 0.00 0.00 0.00
0.99 (0.49; 2.11) 1.22 (0.59; 2.42) 0.64 (0.28; 1.41) 0.62 (0.32; 1.13) 0.87 (0.41; 1.81) 0.01 0.03 0.05
here and favoring denosumab and teriparatide. The rela- feasible (no head-to-head trials available) or indirect com-
tive efficacy of these agents would be best appraised when parison was not feasible (the drug was not connected in a
more practical trials accrue, enrolling typical patients and loop in the evidence network).
measuring fracture outcomes. In addition, this analysis focused on randomized trials
The current study has several limitations. Inference is to limit the impact of bias that threatens internal validity
clearly limited by the imprecise estimates caused by the of the results. However, randomized trials may have lower
small number of events (fractures). Confidence in the con- external validity (applicability) compared with large ob-
clusions of analyses that include indirect comparisons servational studies that may represent a real-world setting
should be lower than that of direct, head-to-head com- and provide important contributions to comparative ef-
parisons. Inconsistency evaluation was limited by several fectiveness research. Cadarette et al. (5) studied elderly
comparisons in which either direct comparison was not enrollees in two statewide pharmaceutical benefit pro-
TABLE 3. Continued
Vitamin D ⴙ
Ibandronatea Alendronateb Vitamin D calcium Calcium P (best) P (2nd best) P (3rd best)
0.00 0.00 0.00
0.79 0.11 0.04
0.02 0.13 0.19
0.00 0.00 0.00
0.04 0.30 0.28
0.05 0.31 0.34
0.09 0.12 0.05
0.89 (0.48; 1.78) 0.00 0.01 0.06
1.14 (0.60; 2.36) 1.29 (1.03; 1.62) 0.00 0.00 0.00
1.06 (0.57; 2.15) 1.19 (1.03; 1.38) 0.93 (0.77; 1.11) 0.00 0.00 0.00
1.13 (0.60; 2.37) 1.28 (1.04; 1.59) 0.99 (0.80; 1.24) 1.07 (0.89; 1.30) 0.00 0.00 0.00
0.96 (0.50; 1.98) 1.08 (0.80; 1.45) 0.84 (0.61; 1.14) 0.91 (0.70; 1.17) 0.85 (0.61; 1.16) 0.00 0.02 0.04
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1878 Murad et al. Drug Treatments to Prevent Fragility Fractures J Clin Endocrinol Metab, June 2012, 97(6):1871–1880
grams and concluded that differences in fracture risk be- found moderate-quality evidence to support the efficacy of
tween risedronate or raloxifene and alendronate were teriparatide, denosumab, alendronate, risedronate, zole-
small, whereas nasal calcitonin recipients had a higher dronate, and ibandronate compared with placebo or vi-
nonvertebral fracture risk. tamin D and calcium. The evidence supporting the efficacy
The results of this network meta-analysis are consistent of raloxifene or bazedoxifene on fractures remains impre-
with those of other evidence synthesis reports. Hopkins et cise due to the small number of fracture events. Vitamin D
al. (47) concluded that teriparatide, zoledronic acid, and and calcium appear to be least effective. However, due
denosumab have the highest probabilities of being most both to the limited number of direct head-to-head trials
efficacious for nonvertebral and vertebral fractures. Ma- and the small number of fracture outcomes in trials avail-
cLean et al. (3) concluded that bisphosphonates and PTH able for analysis, these data are insufficient to determine
were effective in reducing the risk of fractures compared the comparative efficacy of each of the available osteopo-
with placebo but could not provide inference regarding the rosis therapies with respect to fracture outcomes. Al-
relative efficacy of the different agents due to the small though it would be easy to call for more comparative ef-
number of head-to-head trials and of events in these trials. fectiveness research, the reality is that the large sample
Study-level meta-analysis (10) and individual patient data sizes required to generate sufficient fracture outcomes nec-
pooled analysis (48) demonstrated that vitamin D, only if essary to demonstrate a significant difference in fracture
given with calcium, reduces hip fractures and total fractures, risk reduction between two similarly efficacious treat-
and probably vertebral fractures, irrespective of age, sex, or ments would likely prove cost prohibitive and not attrac-
history of previous fractures. Avenell et al. (10) demonstrated tive to sponsors, particularly the pharmaceutical industry.
in their meta-analysis that vitamin D combined with calcium
Importantly, efficacy in fracture reduction is but one of
led to a similar reduction in the risk of hip fracture compared
many considerations when choosing a medication to treat
with that demonstrated in our meta-analysis (relative risk,
osteoporosis. Additional considerations include patient
0.84; 95% CI, 0.73– 0.96; vs. OR, 0.81; 95% CI, 0.68 –
comorbidities, potential side-effect profiles, relative med-
0.96). Consistent with our results, they also demonstrated
ication costs, mode of administration, and both patient
that vitamin D on its own does not reduce the risk of hip,
tolerance and likelihood of medication adherence. For ex-
vertebral, or nonvertebral fractures.
ample, patients with significant gastroesophageal reflux
The present network meta-analysis brings the evidence
symptoms should avoid oral bisphosphonates, those with
base to the present date and allows the evaluation of all the
renal impairment should avoid iv bisphosphonates, and
available interventions including denosumab and SERM.
those who worry the most about unknown side effects of
The potential relative superiority of teriparatide found in
new agents may not opt for denosumab until long-term
this meta-analysis is consistent with a recent randomized
safety data are available (8).
trial that demonstrated lower incidence of new vertebral
fractures compared with risedronate in postmenopausal Both patients and physicians must consider all of these
women after 18 months of therapy (4.4 vs. 9.4%; P ⫽ factors in any informed decision as to which medication is
0.01) (17). best for a particular patient. Given the evidence state, it
seems difficult to justify prescription for particularly ex-
Clinical implications pensive, burdensome, or less safe medicines. If this were
Treatment options to care for people at increased frac- not to be the case, the cost of conducting comparative
ture risk have substantially expanded since the widespread effectiveness research with large sample sizes and number
introduction of oral bisphosphonate therapy in the mid- of events may become justified by the potential cost sav-
1990s, before which there were comparatively few effec- ings in providing higher quality information to decision
tive options for treating this condition. At present, there makers (policymakers, formulary designers, clinicians,
are multiple medication choices across multiple drug and patients). The accompanying guideline from The En-
classes with varying mechanisms of action, modes of ad- docrine Society (9) will provide the practical and clinical
ministration, and levels of efficacy related to fracture out- implications of our findings in men.
comes. Given the limited comparative effectiveness studies
currently available, it remains difficult for clinicians to Conclusions
make informed decisions about which medication or class Teriparatide, bisphosphonates, and denosumab are
of medications is most effective for preventing fragility most effective in reducing the risk of fragility fractures.
fractures in susceptible individuals. Differences in efficacy across drugs are small; therefore,
Herein, we have synthesized and summarized the avail- treatment decisions should also be based on the associated
able evidence to help inform clinical decision making. We harms and costs.
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J Clin Endocrinol Metab, June 2012, 97(6):1871–1880 jcem.endojournals.org 1879
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1880 Murad et al. Drug Treatments to Prevent Fragility Fractures J Clin Endocrinol Metab, June 2012, 97(6):1871–1880
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