1. health and fitness
2. disease
3. cancer

Review
Annals of Internal Medicine
Comparative Effectiveness of Pharmacologic Treatments to
Prevent Fractures
An Updated Systematic Review
Carolyn J. Crandall, MD, MS; Sydne J. Newberry, PhD; Allison Diamant, MD, MSHS; Yee-Wei Lim, MD, PhD; Walid F. Gellad, MD, MPH;
Marika J. Booth, MS; Aneesa Motala, BA; and Paul G. Shekelle, MD, PhD
Background: Osteoporosis is a major contributor to the propensity
to fracture among older adults, and various pharmaceuticals are
available to treat it.
Purpose: To update a review about the benefits and harms of
pharmacologic treatments used to prevent fractures in adults at risk.
Data Sources: Multiple computerized databases were searched between 2 January 2005 and 4 March 2014 for English-language
studies.
Study Selection: Trials, observational studies, and systematic
reviews.
Data Extraction: Duplicate extraction and assessment of data
about study characteristics, outcomes, and quality.
Data Synthesis: From more than 52 000 titles screened, 315 articles were included in this update. There is high-strength evidence
that bisphosphonates, denosumab, and teriparatide reduce fractures
compared with placebo, with relative risk reductions from 0.40 to
0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral
O
steoporosis is a skeletal disorder characterized by
compromised bone strength, increasing the risk for
fracture (1). Risk factors include, but are not limited to,
increasing age, female sex, postmenopause for women, low
body weight, parental history of a hip fracture, cigarette
smoking, race, hypogonadism, certain medical conditions
(particularly rheumatoid arthritis), and certain medications
for chronic diseases (such as glucocorticoids).
During one’s expected remaining life, 1 in 2 postmenopausal women and 1 in 5 older men are at risk for an
osteoporosis-related fracture (2). The increasing prevalence
and cost of osteoporosis have heightened interest in the
effectiveness and safety of the many interventions currently
available to prevent osteoporotic fracture. In 2007, we conducted a systematic review of the comparative effectiveness
of treatments to prevent fractures in men and women with
low bone density or osteoporosis (3, 4). Since that time,
new drugs have been approved for treatment, and new
studies have been published about existing drugs. Additional issues about pharmacologic treatments for osteoporosis that have become particularly salient include the optimal duration of therapy; the safety of long-term therapy;
and the role of bone mineral density (BMD) measurement,
both for screening and for monitoring treatment. Therefore, we updated our original systematic review.
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fractures. Raloxifene has been shown in placebo-controlled trials to
reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use: atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs.
Limitations: Few studies have directly compared drugs used to
treat osteoporosis. Data in men are very sparse. Costs were not
assessed.
Conclusion: Good-quality evidence supports that several medications for bone density in osteoporotic range and/or preexisting hip
or vertebral fracture reduce fracture risk. Side effects vary among
drugs, and the comparative effectiveness of the drugs is unclear.
Primary Funding Source: Agency for Healthcare Research and
Quality and RAND Corporation.
Ann Intern Med. 2014;161:711-723. doi:10.7326/M14-0317
www.annals.org
For author affiliations, see end of text.
This article was published online first at www.annals.org on 9 September 2014.
METHODS
This article is a condensed and further updated version
of an evidence review conducted for the Agency for
Healthcare Research and Quality (AHRQ) Evidence-based
Practice Centers program (5). This article focuses on the
comparative benefits and risks of short- and long-term
pharmacologic treatments for low bone density. In addition, we address issues regarding monitoring and duration
of therapy. For this updated review, we followed the same
methods as our 2007 review, with a few exceptions. A
protocol for this review was developed and posted on the
Effective Health Care Program Web site (6).
Data Sources and Searches
We searched MEDLINE, EMBASE, the Cochrane
Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the ACP Journal Club database, the National Institute for Clinical Excellence, the
See also:
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18 November 2014 Annals of Internal Medicine Volume 161 • Number 10 711
Review
Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures
Food and Drug Administration’s (FDA) MedWatch database, and relevant pharmacologic databases from 2 January
2005 to 3 June 2011. The search strategy followed that of
the original report, with the addition of terms for new
FDA-approved drugs (such as denosumab) and newly reported adverse events. The full search strategies are in our
evidence report (5). We later updated this search to 21
January 2013 and used a machine learning method that a
previous study showed had high sensitivity for detecting
relevant evidence for updating a search of the literature on
osteoporosis treatments (7) and then updated the searches
to 4 March 2014 using the full search strategy.
Study Selection
Eligible studies were systematic reviews and randomized, controlled trials (RCTs) that studied FDA-approved
pharmacotherapy (excluding calcitonin and etidronate) for
women or men with osteoporosis that was not due to
a secondary cause (such as glucocorticoid therapy and
androgen-deprivation therapy) and also measured fractures
as an outcome at a minimum follow-up of 6 months. In
addition, we included observational studies with more than
1000 participants for adverse events and case reports for
rare events. As in our original review, only Englishlanguage studies were included.
Data Extraction and Quality Assessment
Reviews were done in duplicate by pairs of reviewers.
Study characteristics were extracted in duplicate, and outcomes data (both benefits and harms) were extracted by the
study statistician. Study quality was assessed as it was in the
2007 report using the Jadad scale for clinical trials (with
several questions added to assess allocation concealment
and other factors) and the Newcastle–Ottawa Scale for observational studies (8, 9). Systematic reviews were assessed
using a modified version of the 11 AMSTAR (A Measurement Tool to Assess Systematic Reviews) criteria (the modifications included eliminating the requirements to list all
of the excluded studies and assess the conflicts of interest
for all of the included studies) (10). The assessments of
efficacy and effectiveness used reduction in fracture (all,
vertebral, nonvertebral, spine, hip, wrist, or other) as the
outcome (studies reporting changes in BMD but not fracture were excluded).
Data Synthesis and Analysis
Evidence on efficacy and effectiveness was synthesized
narratively. For adverse events, we pooled data as in the
2007 report: We compared agent versus placebo and agent
versus agent for agents within the same class and across
classes. For groups of events that occurred in 3 or more
trials, we estimated the pooled odds ratio (OR) and its
associated 95% CI. Because many events were rare, we
used exact conditional inference to perform the pooling
rather than applying the usual asymptotic methods that
assume normality. StatXact PROCs software was used for
the analysis (11, 12). Large cohort and case– control studies
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were included to assess adverse events. Strength of evidence
was assessed using the criteria of the Agency for Healthcare
Research and Quality Evidence-based Practice Centers
program, which are similar to those proposed by the Grading of Recommendations Assessment, Development and
Evaluation (GRADE) Working Group (13).
Role of the Funding Source
The update that included studies identified in the 3
June 2011 search was funded by AHRQ. Subsequent updating received no external funding. Although AHRQ formulated the initial study questions for the original report,
it did not participate in the literature search, determination
of study eligibility criteria, data analysis, or interpretation
of the data. Staff from AHRQ reviewed and provided comments on the report.
RESULTS
The first search yielded 26 366 titles, 2440 of which
were considered potentially relevant (Figure). Of these,
661 full-text articles were reviewed, resulting in 255 articles
that were included in the update report. Of these, 174
articles were relevant to this article. The second update
search plus hand searching initially yielded 16 589 titles,
and machine learning and full-text review identified 107 as
relevant. The third update yielded 12 131 titles. After title,
abstract, and full-text screening, 34 were relevant. Thus,
55 086 titles were screened and 315 articles met eligibility
criteria for inclusion. Not every eligible study is cited in
this article. A complete list of studies that met eligibility
criteria is available at www.rand.org/health/centers/epc.
Fracture Prevention
Our previous review (3) identified 76 randomized trials and 24 meta-analyses and concluded that there was
good-quality evidence that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid
hormone, and raloxifene prevented osteoporotic fractures,
although not all of these agents prevented hip fractures.
The principal new efficacy findings since that time are additional data about zoledronic acid and data about a new
agent, denosumab (Tables 1 and 2). The data for zoledronic acid came from 6 placebo-controlled studies of various doses in postmenopausal women (14 –19), the 2 largest of which enrolled 7230 women (15) and 2127 women
(14). Both studies showed statistically significant reductions in nearly all types of fractures assessed, with relative
risk reductions ranging from 0.23 to 0.73 at time points
from 24 to 36 months after initiation of treatment. The
data for denosumab came from 2 placebo-controlled trials
in postmenopausal women, one small (332 enrolled
women) (20) and one much larger that followed 7521
women for 36 months (21). This latter study found statistically significant reductions in each anatomical fracture
type measured (hip, nonvertebral, vertebral, and new clinical vertebral), with hazard ratios of 0.31 to 0.80. Many
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Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures
Review
Figure. Summary of evidence search and selection.
Titles and abstracts identified for abstract review for
LBD update report on 12 November 2011 (n = 2440)
Titles and abstracts
excluded (n = 1779)
Not osteoporosis: 535
Design: 772
No fracture outcomes: 262
Population: 75
Not found: 8
LBD 1*: 127
Articles accepted for detailed review (n = 661)
Excluded
(n = 406)
Accepted for LBD
update report (n = 255)
Titles and abstracts
accepted for review
from update searches
on 4 March 2014
(n = 283)
Topics excluded from review
(n = 81)
Adherence: 67
Vitamin D and/or calcium: 8
Discontinuation, monitoring,
duration of therapy,
FRAX: 4
HRT or exercise: 2
Excluded (n = 142)
Did not meet inclusion/
exclusion criteria of the
LBD report: 72
Adherence, vitamin D and/or
calcium, discontinuation,
monitoring, duration of
therapy, FRAX, HRT, and
exercise: 70
Included in review
(n = 174)
Accepted for review
(n = 141)
Accepted for synthesis (n = 315)
FRAX ⫽ Fracture Risk Assessment Tool; HRT ⫽ hormone replacement therapy; LBD ⫽ low bone density.
* Original LBD report (4).
secondary analyses and open-label extension results of this
trial report the effectiveness of denosumab in various subpopulations and other circumstances (22–28).
Despite some difficulties in comparing results across
trials because of differences in the outcomes reported,
high-strength evidence shows that bisphosphonates (alendronate, ibandronate, risedronate, and zoledronic acid),
denosumab, and teriparatide (the 1,34 amino acid fragment of the parathyroid hormone) reduce fractures compared with placebo in postmenopausal women with osteoporosis, with relative risks for fractures generally in the
range of 0.40 to 0.60 for vertebral fractures and 0.60 to
0.80 for nonvertebral fractures. This range translates into a
number needed to treat of 60 to 89 to prevent 1 vertebral
fracture and 50 to 67 to prevent 1 hip fracture over 1 to 3
years of treatment, using a pooled average of the incidence
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of these fractures in the placebo groups from included
studies. The effect of ibandronate on hip fracture risk reduction is unclear because hip fracture was not a separately
reported outcome in placebo-controlled trials of this agent.
The selective estrogen receptor modulator raloxifene has
been shown in placebo-controlled trials to reduce only vertebral fractures; reduction in the risk for hip or nonvertebral fractures was not statistically significant.
There is only one randomized, controlled trial of men
with osteoporosis that was designed with a primary fracture
reduction outcome. Nearly 1200 men with osteoporosis
were randomly assigned to placebo or zoledronic acid intravenously once per year for 2 years. At follow-up, 1.6%
of treated men had new radiologically detected vertebral
fractures, compared with 4.9% of men treated with placebo, with a relative risk of 0.33 (95% CI, 0.16 to 0.70).
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Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures
Table 1. Principal Conclusions About Drug Efficacy/Effectiveness and Adverse Events
Variable
Outcome
Strength of Evidence
Magnitude of Effect
Vertebral
Fractures in women with osteoporosis
Strong
Number needed to treat, 60–89 to prevent
1 fracture over 1–3 y of treatment
Nonvertebral fracture in women with osteoporosis
Strong
Number needed to treat, 50–60 to prevent
1 fracture over 1–3 y of treatment
Vertebral
Fractures in men with osteoporosis
Moderate
RR, 0.33
Number needed to treat, 30 (limited to
1 study in men of 24-mo duration)
Mild upper gastrointestinal symptoms
Strong
OR, 1.6–3.3
72–956 events per 1000 persons
Hot flashes, thromboembolic events
Strong
Teriparatide
Headache
Strong
Teriparatide
Hypercalcemia
Strong
Zoledronic acid
Hypocalcemia
Strong
Zoledronic acid
Influenza-like symptoms
Strong
Denosumab
Infection
Moderate
Bisphosphonates
Bisphosphonates
Atypical subtrochanteric fracture
Osteonecrosis of the jaw
Low
Low
OR, 1.6
24–35 events per 1000 persons
OR, 1.5
511–679 events per 1000 persons
OR, 13
537–820 events per 1000 persons
OR, 7
5–118 events per 1000 persons
OR, 6.4
728–896 events per 1000 persons
RR, 1.3
Number needed to harm, 118
2–100 per 100 000 women
0.03%–4.30%
Efficacy/Effectiveness
Alendronate
Ibandronate
Risedronate
Zoledronic acid
Denosumab
Teriparatide
Raloxifene
Alendronate
Risedronate
Zoledronic acid
Denosumab
Teriparatide
Zoledronic acid
Adverse event
Bisphosphonates
Denosumab
Teriparatide
Raloxifene
OR ⫽ odds ratio; RR ⫽ risk ratio.
Approximately 1.0% of actively treated men, compared
with 1.8% of men treated with placebo, had a clinical
vertebral or nonvertebral fracture (hazard ratio, 0.6 [CI,
0.2 to 1.5]) (29).
Comparative Effectiveness
Head-to-head comparative effectiveness studies assessing fracture outcomes are rare, have either not reported
statistical testing or fracture outcomes between groups
(30), have not found significant differences (3), or have
analyzed the comparisons on a per-protocol rather than an
intention-to-treat basis (31, 32). Thus, there have been
several attempts to estimate comparative effectiveness using
network meta-analysis and indirect or mixed treatment
comparisons. A recent network meta-analysis of 116
placebo-controlled or head-to-head trials assessing alendronate, risedronate, ibandronate, zoledronic acid, raloxifene,
denosumab, teriparatide, vitamin D, and calcium concluded that any of the drugs were likely more effective than
vitamin D or calcium; the evidence supporting raloxifene
was not as strong as the evidence for the other drugs; and
differences in vertebral and nonvertebral fracture risk reduction among any of the bisphosphonates, denosumab, or
teriparatide were not consistent or statistically significant
(AMSTAR score, 10 of 11) (33).
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A second network meta-analysis (AMSTAR score, 6 of
11) included 30 RCTs and found no significant differences
in nonvertebral fracture risk in the indirect comparisons
among alendronate, risedronate, etidronate, ibandronate,
zoledronic acid, raloxifene, denosumab, teriparatide, or
strontium, although the authors noted that etidronate,
ibandronate, and raloxifene lack direct evidence of superiority to placebo in preventing nonvertebral fractures (34).
A third network meta-analysis, both sponsored by and
including coauthors from the manufacturer of one drug,
included 21 studies and likewise found no statistically significant difference in indirect or mixed treatment comparisons in nonvertebral fracture risk reduction among alendronate, risedronate, etidronate, ibandronate, zoledronic
acid, raloxifene, denosumab, teriparatide, or strontium.
These authors also noted that etidronate, raloxifene, and
ibandronate did not have direct evidence of a reduction in
nonvertebral fractures relative to placebo (AMSTAR score,
7 of 11) (35).
A fourth network meta-analysis (AMSTAR score, 3 of
11), this time assessing alendronate, risedronate, ibandronate, zoledronic acid, and denosumab and restricting inclusion to studies that reported clinical and morphometric
vertebral fractures and had a treatment period of at least 3
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Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures
years, included 9 RCTs and reported no statistically significant differences among drugs in the mixed treatment comparison (36).
A fifth network meta-analysis, sponsored by and including authors from the manufacturer of one drug, included 8 RCTs to assess the relative effectiveness of
alendronate, ibandronate, risedronate, etidronate, and zoledronic acid on many fracture outcomes (AMSTAR score, 6
of 11). Other than the sponsor’s drug and the outcome of
morphometric vertebral fractures, this analysis did not find
any consistent significant differences among drugs for the
various fracture outcomes (37).
All of these network meta-analyses are limited by the
dearth of head-to-head studies; nevertheless, their conclusions are consistent with our narrative synthesis of the evidence. Raloxifene does not prevent nonvertebral fractures,
and there is less evidence supporting nonvertebral fracture
reduction efficacy for ibandronate than for the other bisphosphonates, denosumab, or teriparatide. Other differences in comparative effectiveness among drugs are likely
to be small.
Adverse Events
Atypical Subtrochanteric Fractures
An important new potential adverse event is the increased risk for atypical subtrochanteric fractures seen in
patients treated with bisphosphonates (Table 3). At present, these associations come entirely from observational
studies, and results are not completely consistent (38 –71).
An increased risk has not been seen in clinical trials, although even an analysis of data aggregated from 3 large
trials (a total of 14 195 women) was underpowered to detect an effect (pooled relative risk, 1.33 [CI, 0.12 to 14.7])
(61). A systematic review of case and case series studies
(AMSTAR score, 7 of 9) (66) identified 141 women with
this fracture, and the FDA issued a warning about the
possible link between bisphosphonate use and this adverse
event (72).
Since then, a recent meta-analysis of 5 case– control
studies and 6 cohort studies (AMSTAR score, 10 of 11)
found an overall pooled risk ratio of 1.70 (CI, 1.22 to
2.37) (73). A 2013 analysis of the data from the FDA
Review
Adverse Event Reporting System and other international
drug safety databases reported a proportional reporting ratio of 4.51 (CI, 3.44 to 5.92) (74) for nonhealing femoral
fractures. A 2014 update of the American Society for Bone
and Mineral Research task force concluded that evidence
for a relationship has become more compelling since its
2010 report, particularly with longer bisphosphonate use
(75). Despite the limitation created by the variation in the
definition of atypical fracture across studies, data are sufficient to conclude that bisphosphonate use, especially longterm, increases risk for atypical femoral fractures, although
the strength of evidence is low. It is important to note that
the absolute risk for atypical fractures is 30- to 100-fold
less than the risk for hip fracture among untreated persons
at risk. In one study from Kaiser Permanente Southern
California of 1 835 116 women aged 45 years or older over
5 years, there were 7430 typical hip fractures and 142
atypical femur fractures. The finding that the incidence
rate of atypical fractures increased from 1.78 per 100 000
for women receiving bisphosphonates for less than 2 years
to more than 100 per 100 000 for women receiving bisphosphonates for 8 years or more supports the idea that
treatment duration may be a factor (52). Use of denosumab has also been linked with atypical femoral fractures
(26).
Cancer
We found low-strength signals of potential associations with various types of cancer, but additional data are
needed. Four large observational studies have assessed a
possible association between the use of bisphosphonates
and esophageal cancer, 2 of which reported an increased
risk (76, 77) and 2 of which did not (78, 79). Several large
observational studies found that bisphosphonate use was
associated with either no increased risk or, in some cases, a
statistically significant decrease in the risk for all types of
cancer in general (80 – 83) and certain types of cancer, specifically breast (81), colon, and other gastrointestinal cancer (80, 84). A meta-analysis of 4 studies (AMSTAR score,
8 of 11) concluded that there were statistically significantly
increased odds (1.74) for esophageal cancer in patients
Table 2. Principal Conclusions About Monitoring and Treatment Duration
Conclusion
Strength of Evidence
Estimate of Effect
Monitoring is likely not needed in most women
Moderate
How long to treat is unknown, but high-risk patients
may benefit from treatment longer than 5 y
Low
Patients with T-scores greater than ⫺1.5 only rarely progress to
osteoporosis in 15 y; patients receiving treatment benefit even if
their BMD does not increase; the only reported benefit of monitoring
on treatment is in women receiving alendronate for 5 y who had a
vertebral fracture at baseline
Reported benefit of treatment beyond 5 y is greatest in women treated
with alendronate who had a baseline vertebral fracture (before
treatment) and a femoral neck BMD T-score at 5 y that is less than
⫺2.5, in whom continued alendronate treatment for an additional
5 y (total of 10 y) decreased new vertebral fracture from 11.1% to
5.3% compared with placebo
BMD ⫽ bone mineral density.
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Table 3. Selected Adverse Events, by Drug Compared With Placebo
Adverse Event, by Drug
Included Studies, n
Study Participants, n
Alendronate
Mild upper gastrointestinal symptoms
50
22 549
1.07 (1.01–1.14)
Raloxifene
Cardiovascular (serious)
Thromboembolic events
Pulmonary embolism
Cerebrovascular death
Hot flashes
Death, not otherwise specified
8
4
2
8
4
23 747
21 588
14 112
7392
14 504
1.63 (1.36–1.98)
1.82 (1.16–2.92)
1.56 (1.04–2.39)
1.58 (1.35–1.84)
1.38 (1.04–1.83)
Ibandronate
Myalgias, cramps, and limb pain
2
3489
2.25 (1.57–3.29)
Zoledronic acid
Atrial fibrillation
Arthritis and arthralgias
Headaches
Hypocalcemia
Uveitis or ocular events possibly or likely related to the study drug
Composite of symptoms
Arthralgia
Influenza-like symptoms
Myalgia
Nausea
Pyrexia
Headache
Chills
2
6
4
2
2
8
6
5
5
2
5
4
1
9876
11 171
10 773
2173
4112
11 676
11 171
10 695
11 065
684
11 065
10 773
392
Denosumab
Mild upper gastrointestinal symptoms
Rash/eczema
3
3
8454
8454
1.74 (1.29–2.38)
1.96 (1.46–2.66)
Teriparatide
Upper gastrointestinal symptoms
Renal symptoms
Headaches
Hypercalcemia
Hypercalciuria
4
2
4
5
2
5184
4169
5184
6374
4136
3.26 (2.82–3.78)
2.36 (2.01–2.77)
1.46 (1.27–1.69)
12.90 (10.49–16.00)
2.44 (2.08–2.86)
OR (95% CI)
1.45 (1.14–1.86)
2.82 (2.32–3.45)
3.18 (2.57–3.97)
7.22 (1.81–42.70)
12.1 (1.78–516.00)
6.39 (5.76–7.09)
2.82 (2.32–3.45)
4.98 (3.82–6.58)
5.56 (4.46–6.99)
8.13 (3.57–21.7)
7.94 (6.51–9.74)
3.18 (2.57–3.97)
35.3 (11.19–180.00)
OR ⫽ odds ratio.
treated with bisphosphonates (85), but another metaanalysis (AMSTAR score, 7 of 11) that included the same
4 studies and 3 additional ones found no association of risk
for esophageal cancer with bisphosphonate use (86). The
FDA has not concluded that patients receiving oral bisphosphonate drugs have an increased risk for esophageal
cancer. An evaluation of osteosarcoma and teriparatide
showed no relationship at 7-year follow-up (87).
Cardiac Risks
An adverse event prominently discussed in 2007 was
the potential for bisphosphonate use to cause atrial fibrillation. In 2008, the FDA concluded that “there was no
clear association” between bisphosphonate use and atrial
fibrillation. Since that time, most (88 –92) but not all (93)
original studies and meta-analyses have concluded that
there is no increased risk, and concern about atrial fibrillation has faded. A retrospective cohort study using Danish
registry data reported on the risk for a diagnosis of heart
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failure after bisphosphonate prescription. Risk increased
with risedronate use and decreased with alendronate use,
rendering interpretation of a causal relationship difficult
(94).
Gastrointestinal Side Effects
In our previous review, we did a meta-analysis of adverse events that included 417 randomized trials. In this
paper, we identified 31 new articles reporting adverse
events, 17 of which contributed to updated pooled analyses
(18, 32, 80, 95–108). These updated analyses showed increased risk for mild upper gastrointestinal side effects with
use of alendronate (OR, 1.07 [CI, 1.01 to 1.14]), teriparatide (OR, 3.26 [CI, 2.82 to 3.78]), and denosumab (OR,
1.74 [CI, 1.29 to 2.38]). A network meta-analysis attempted to assess the comparative gastrointestinal safety of
bisphosphonates and included 50 RCTs (49 of which were
also included in our pooled analyses). For the outcome
“treatment discontinuation due to adverse events,” this
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Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures
network meta-analysis did not find any statistically significant differences among any of the bisphosphonates included in our key questions (109). Consistent with our
2007 meta-analysis, a case–control study (804 case and
12 787 control participants) found no statistically significant association between oral alendronate or risedronate
use and the risk for subsequent hospitalization for serious
upper gastrointestinal diagnoses (perforations, ulcers, and
bleeding) (110).
Infection
A pooled analysis of 4 trials of denosumab found an
increased risk for infection (risk ratio [RR], 1.28 [CI, 1.02
to 1.60]) (111), and the FDA has issued a Risk Evaluation
and Mitigation Strategy for the drug. In the largest denosumab trial, there were imbalances between patients treated
with denosumab and those receiving placebo for cellulitis,
erysipelas, serious ear infections, infective arthritis, and endocarditis. A causal relationship has not been established.
Osteonecrosis of the Jaw
At the time of our previous review, 41 cases of osteonecrosis of the jaw had been identified, nearly all associated
with the use of intravenous bisphosphonates. Since that
time, 23 publications have assessed this association (112–
134) (not counting individual case reports), including a
case series of 2408 cases of osteonecrosis of the jaw that
found that 88% were associated with intravenous bisphosphonates and 89% of patients were being treated for a
malignant condition (135), a survey of practitioners that
estimated an incidence of 28 cases per 100 000 personyears of exposure (129), and 4 systematic reviews (127,
132–134). The most recent of these systematic reviews
identified 9 and 12 articles (133, 134), respectively, of
studies about osteonecrosis of the jaw in noncancer patients. The first review (133) (AMSTAR score, 6 of 9)
reported that limitations in case definition and the identification of the denominator led to wide variation in the
reported incidence, from 0.028% to 4.3%, and these authors refrained from statistical pooling. The second review
(134) (AMSTAR score, 6 of 11) pooled 12 studies with
high heterogeneity and found an OR of 2.32 (CI, 1.30 to
3.91; I 2 ⫽ 41%). This association was of similar magnitude in multiple sensitivity analyses. Osteonecrosis of the
jaw has also been reported with denosumab use (26).
Other
Our pooled analyses showed teriparatide to be associated with an increased risk for hypercalcemia (OR, 12.90
[CI, 10.49 to 16.00]) and zoledronic acid (OR, 7.22 [CI,
1.81 to 42.70]) to be associated with an increased risk for
hypocalcemia (however, 85% of patients did not require
supplemental calcium). Hot flashes (OR, 1.58 [CI, 1.35 to
1.84]), thromboembolic events (OR, 1.63 [CI, 1.36 to
1.98]), pulmonary embolism (OR, 1.82 [CI, 1.16
to 2.92]), and fatal strokes (OR, 1.56 [CI, 1.04 to 2.39])
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Review
have been associated with raloxifene use. Headaches (OR,
1.46 [CI, 1.27 to 1.69]) and renal-related adverse events
have been associated with teriparatide use. Zoledronic acid
infusion is associated with a constellation of symptoms that
have been described as myalgia, arthralgia, pyrexia, chills,
and influenza-like symptoms. A composite of these symptoms has a pooled OR of 6.39 (CI, 5.76 to 7.09). Table 1
displays the results of our pooled analyses of RCTs for all
adverse events (adverse events were included if at least 3
trials discussed that event or if the RCTs regarding the
event had sample sizes of at least 1000 patients in both the
treatment and placebo group).
A study using a national registry in Denmark reported
that the risk for inflammatory eye reactions in certain patients treated with bisphosphonates is low (136).
Treatment Duration
Only 2 large RCTs have compared shorter with longer
durations of therapy. In the Fracture Intervention Trial
Long-Term Extension (FLEX) study (the original RCT
compared alendronate and placebo for 5 years among postmenopausal women), several subsequent analyses have addressed longer (10-year) versus shorter (5-year) therapy
with alendronate. At 10-year follow-up, the cumulative
risk for nonvertebral fractures was not significantly different between those continuing (19%) and discontinuing
(19%) alendronate (137). However, among women who
continued alendronate, there was a significantly lower risk
for clinically recognized vertebral fractures (5.3% for placebo vs. 2.4% for alendronate; RR, 0.45 [CI, 0.24 to
0.85]) but no significant reduction in morphometric vertebral fractures.
In a recent post hoc analysis of the FLEX data, investigators assessed whether baseline BMD or preexisting fracture could influence the effects of longer duration of therapy (10 vs. 5 years). Among women without vertebral
fracture at FLEX baseline, alendronate continuation reduced nonvertebral fracture among women with FLEX
baseline femoral neck T-scores of ⫺2.5 or less (RR, 0.50
[CI, 0.26 to 0.96]) but not among women with T-scores
between ⫺2.5 and ⫺2.0 (RR, 0.79 [CI, 0.37 to 1.66]) or
those with T-scores of greater than ⫺2.0 (RR, 1.41 [CI,
0.75 to 2.66]; P for interaction, 0.019). Among women
with a prevalent vertebral fracture at baseline and a BMD
T-score at 5 years of ⫺2.5 or less, continued use of alendronate for 5 years decreased the incidence of new clinical
vertebral fractures from 11.1% to 5.3%, compared with
placebo. The investigators concluded that continuing with
alendronate for 10 years instead of stopping after 5 years
reduced nonvertebral fracture risk in women without prevalent vertebral fracture whose femoral neck T-scores,
achieved after 5 years of alendronate, were ⫺2.5 or less but
did not reduce risk for nonvertebral fracture risk among
women without prevalent vertebral fractures whose
T-scores were greater than ⫺2.0 (138).
18 November 2014 Annals of Internal Medicine Volume 161 • Number 10 717
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Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures
In the Health Outcomes and Reduced Incidence With
Zoledronic Acid Once Yearly Pivotal Fracture Trial, approximately 1200 women who had received zoledronic
acid for 3 years were randomly assigned to continue for
another 3 years or be switched to placebo. Incidence of
radiographically detected vertebral fracture was lower in
the patients continuing zoledronic acid (3.0% vs. 6.2% in
patients receiving placebo; OR, 0.51 [CI, 0.26 to 0.95]),
but there were no differences between groups in clinical
vertebral fractures, hip fractures, nonvertebral fractures, or
all clinical fractures (139).
In a recent FDA review on this subject (which involved the FDA’s own analysis and pooling of data from
these 3 trials with an older and much smaller study of
risedronate [140]), the FDA found that the rate of vertebral and nonvertebral fractures in patients who received
bisphosphonates for more than 6 years was 9.3% to 10.6%
compared with 8.0% to 8.8% for patients who switched to
placebo. The FDA concluded that “these data raise the
question of whether continued bisphosphonate therapy
imparts additional fracture-prevention benefit, relative to
cessation of therapy after 5 years” (141). In an accompanying commentary, leading osteoporosis experts cautioned
that these data came primarily from 2 large studies of alendronate and zoledronic acid, which were subsets of the
original randomized cohorts, that they should not be extended to other bisphosphonates, and that FLEX patients
with a BMD T-score of ⫺2.5 or less received added benefits from continuing alendronate therapy beyond 5 years
(142).
Dual-Energy X-Ray Absorptiometry Monitoring
Little direct research has been done on the frequency
of monitoring for osteoporosis or how often patients
should be monitored once they begin antiresorptive therapy. Two population studies of persons not taking osteoporosis treatment showed that frequent monitoring for the
development of osteoporosis may not be necessary, except
in women with T-score of ⫺2.0 to ⫺2.49 (143, 144). For
patients receiving antiresorptive therapy for whom serial
BMD measurements have not shown an increase, or have
even shown decrease in BMD, statistically significant benefits are still obtained in terms of fracture reduction (145–
150). Despite a lack of evidence supporting frequent monitoring, one study found that among 549 women being
followed at an academic medical center, patients received
an average of 3.0 dual-energy x-ray absorptiometry scans
over a mean of 2.4 years (for example, an average of ⬎1
per year). A chart review of a random sample of 92 patients
found that, for these women, the primary rationale listed
for 177 of 196 scans (90%) was that they were “due”; no
treatment change was made after 84% of the scans (151).
This single-site study cannot support strong conclusions,
but does highlight the need for more studies about the
appropriate use of dual energy x-ray absorptiometry scans.
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DISCUSSION
The principal conclusions of this update are presented
in Tables 1 and 2. Compared with the evidence available
at the time of the previous report, additional evidence has
emerged about differences in antifracture efficacy among
pharmacologic agents used to treat osteoporosis. Nonetheless, data about the comparative effectiveness or efficacy
among agents are thin, and it is likely that differences
among the bisphosphonates, denosumab, and teriparatide
are modest. The side effect profiles vary among drugs, but
many are associated with gastrointestinal effects. Bisphosphonate and possibly denosumab use carry the risk for very
rare side effects, such as atypical subtrochanteric fracture or
osteonecrosis of the jaw. There is evidence that women
with an initial T-score of ⫺1.49 or greater do not benefit
from repeated BMD reassessment in less than 15 years.
Among persons receiving FDA-approved osteoporosis
pharmacotherapy, changes in BMD are not good predictors of antifracture effects. Likewise, the optimal duration
of therapy remains murky, although evidence suggests that,
at least for alendronate, some groups of patients can have
the drug safely discontinued after 5 years of treatment.
There are many limitations to our review. The most
important of these is the dearth of head-to-head comparisons of the benefits and harms of the agents. This has led
several investigators to estimate comparative effectiveness
using indirect methods. Although no consistent differences
in efficacy have been found, this does not constitute proof
that they do not exist. The lack of data in men leaves
clinicians and policymakers to try to extrapolate from data
in women, which may not be valid. Additional limitations
common to all systematic reviews are the possibility of
publication bias and heterogeneity in the definition of outcomes and adverse events. Limitations of this review include our reliance on English-language publications and no
assessment of costs.
Osteoporosis treatment is an area of very active research. In addition to published studies of new drugs and
combinations of drugs being tested for efficacy (152–155),
studies are ongoing about the comparative effectiveness of
some agents (156), the treatment of men (157), and the
optimal duration of treatment (158).
From David Geffen School of Medicine at the University of California,
Los Angeles, and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; RAND Corporation, Santa Monica, California; Saw Swee Hock School of Public Health, National University of
Singapore, Singapore; and RAND Corporation, Pittsburgh Veterans Affairs Medical Center, and the Center for Health Equity Research and
Promotion, Pittsburgh, Pennsylvania.
Acknowledgment: The authors acknowledge Roberta Shanman, MLS,
for conducting the update searches and Kanaka Shetty, MD, and Michael Scarpati, PhD, for the use of machine learning for the 2013 update
searches. In addition, they acknowledge the guidance provided by the
technical expert panel members, Roberta Biegel, MA; Bruce Ettinger,
www.annals.org
Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures
MD; Theodore Hahn, MD; Marc Hochberg, MD, MPH; Hau
Liu, MD; Catherine MacLean, MD, PhD; Paul Miller, MD; Eric
Orwoll, MD; Marcel E. Salive, MD, MPH; and Daniel Solomon, MD,
MPH.
Grant Support: By the Agency for Healthcare Research and Quality
(AHRQ) (HHSA290200710062I). No statement in this article should
be construed as an official position of AHRQ or the U.S. Department of
Health and Human Services.
Disclosures: All authors received grant support from AHRQ during the
conduct of the study. Dr. Gellad reports grant support from Express
Scripts outside the submitted work. Dr. Shekelle reports royalties from
UpToDate outside the submitted work and was an author of an American College of Physicians guideline on this topic. Disclosures can also be
viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms
.do?msNum⫽M14-0317.
Requests for Single Reprints: Carolyn J. Crandall, MD, MS, Professor
of Medicine, David Geffen School of Medicine, Division of General
Internal Medicine & Health Services Research, University of California,
Los Angeles, 911 Broxton Avenue, 1st Floor, Los Angeles, CA 90024;
e-mail, [email protected].
Current author addresses and author contributions are available at
www.annals.org.
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18 November 2014 Annals of Internal Medicine Volume 161 • Number 10 723
Annals of Internal Medicine
Current Author Addresses: Drs. Crandall and Diamant: David Geffen
School of Medicine, Division of General Internal Medicine & Health
Services Research, University of California, Los Angeles, 911 Broxton
Avenue, 1st Floor, Los Angeles, CA 90024.
Dr. Newberry, Ms. Booth, and Ms. Motala: RAND Corporation, 1776
Main Street, Santa Monica, CA 90401.
Dr. Lim: Saw Swee Hock School of Public Health, National University
of Singapore, Singapore MD3, 16 Medical Drive, Singapore 117597.
Dr. Gellad: Pittsburgh Veterans Affairs Medical Center and the Center
for Health Equity Research and Promotion, University Drive, Pittsburgh, PA 15240.
Dr. Shekelle: Veterans Affairs Los Angeles Healthcare System, 11301
Wilshire Boulevard, Los Angeles, CA 90073.
www.annals.org
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Author Contributions: Conception and design: C.J. Crandall, S.J. New-
berry, A. Diamant, Y.W. Lim, P.G. Shekelle.
Analysis and interpretation of the data: C.J. Crandall, S.J. Newberry, A.
Diamant, Y.W. Lim, W.F. Gellad, M.J. Booth, P.G. Shekelle.
Drafting of the article: C.J. Crandall, S.J. Newberry, A. Diamant, M.J.
Booth, A. Motala, P.G. Shekelle.
Critical revision of the article for important intellectual content: C.J.
Crandall, S.J. Newberry, A. Diamant, W.F. Gellad, P.G. Shekelle.
Final approval of the article: C.J. Crandall, S.J. Newberry, A. Diamant,
W.F. Gellad, P.G. Shekelle.
Statistical expertise: M.J. Booth.
Obtaining of funding: P.G. Shekelle.
Administrative, technical, or logistic support: A. Motala, P.G. Shekelle.
Collection and assembly of data: S.J. Newberry, A. Diamant, Y.W. Lim,
W.F. Gellad, A. Motala, M.J. Booth, P.G. Shekelle.
18 November 2014 Annals of Internal Medicine Volume 161 • Number 10