Content uploaded by Robert H Hopkins
Author content
All content in this area was uploaded by Robert H Hopkins on Mar 19, 2015
Content may be subject to copyright.
Pharmacologic Treatment of Low Bone Density or Osteoporosis to
Prevent Fractures: A Clinical Practice Guideline from the American
College of Physicians
Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Paul Shekelle, MD, PhD; Robert Hopkins Jr., MD; Mary Ann Forciea, MD; and
Douglas K. Owens, MD, MS, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians*
Description: The American College of Physicians (ACP) developed
this guideline to present the available evidence on various pharma-
cologic treatments to prevent fractures in men and women with
low bone density or osteoporosis.
Methods: Published literature on this topic was identified by using
MEDLINE (1966 to December 2006), the ACP Journal Club data-
base, the Cochrane Central Register of Controlled Trials (no date
limits), the Cochrane Database of Systematic Reviews (no date
limits), Web sites of the United Kingdom National Institute of
Health and Clinical Excellence (no date limits), and the United
Kingdom Health Technology Assessment Program (January 1998 to
December 2006). Searches were limited to English-language publi-
cations and human studies. Keywords for search included terms for
osteoporosis, osteopenia, low bone density, and the drugs listed in
the key questions. This guideline grades the evidence and recom-
mendations according to the ACP’s clinical practice guidelines grad-
ing system.
Recommendation 1: ACP recommends that clinicians offer phar-
macologic treatment to men and women who have known osteo-
porosis and to those who have experienced fragility fractures
(Grade: strong recommendation; high-quality evidence).
Recommendation 2: ACP recommends that clinicians consider
pharmacologic treatment for men and women who are at risk for
developing osteoporosis (Grade: weak recommendation; moderate-
quality evidence).
Recommendation 3: ACP recommends that clinicians choose
among pharmacologic treatment options for osteoporosis in men
and women on the basis of an assessment of risk and benefits in
individual patients (Grade: strong recommendation; moderate-
quality evidence).
Recommendation 4: ACP recommends further research to evalu-
ate treatment of osteoporosis in men and women.
Ann Intern Med. 2008;149:404-415. www.annals.org
For author affiliations, see end of text.
See related article in 5 February 2008 issue (volume 148, pages 197-213).
The National Institutes of Health’s consensus conference
(1) defined osteoporosis as “a skeletal disorder charac-
terized by compromised bone strength predisposing to an
increased risk for fracture. Bone strength reflects the inte-
gration of two main features: bone density and bone quality.
. . . Bone quality refers to architecture, turnover, damage
accumulation (e.g., microfractures), and mineralization.”
Although osteoporosis can affect any bone, the hip, spine,
and wrist are most likely to be affected. Osteoporosis af-
fects an estimated 44 million Americans or 55% of people
50 years of age or older. Another 34 million Americans are
estimated to have low bone mass, meaning that they are at
an increased risk for osteoporosis.
Osteoporosis can be diagnosed by the occurrence of fra-
gility fracture. In patients without fragility fracture, osteopo-
rosis is often diagnosed by low bone density. Dual x-ray ab-
sorptiometry (DXA) is the current gold standard test for
diagnosing osteoporosis in people without an osteoporotic
fracture. Dual x-ray absorptiometry results are scored as stan-
dard deviations (SDs) from a young healthy norm (usually
female) and reported as T-scores. For example, a T-score of
⫺2 indicates a bone mineral density that is 2 SDs below the
comparative norm. The international reference standard for
the description of osteoporosis in postmenopausal women and
in men age 50 years or older is a femoral neck bone mineral
density of 2.5 SD or more below the young female adult
mean (2). Low bone density, as measured by DXA, is an
imperfect predictor of fracture risk, identifying fewer than half
the people who go on to have an osteoporotic fracture.
Screening guidelines for women are well established (3), and
* This paper, written by Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Paul Shekelle, MD, PhD; Robert Hopkins Jr., MD; Mary Ann Forciea, MD; and Douglas K. Owens,
MD, MS, was developed for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP): Douglas K. Owens, MD, MS (Chair); Donald E. Casey Jr.,
MD, MPH, MBA; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Mary Ann Forciea, MD; Lakshmi Halasyamani, MD; Robert H. Hopkins Jr., MD; William Rodriguez-Cintron,
MD; and Paul Shekelle, MD, PhD. Approved by the ACP Board of Regents on 12 May 2008.
See also:
Print
Summary for Patients.......................I-46
Web-Only
CME quiz
Conversion of graphics into slides
ACP
Clinical Practice
GUIDELINES
American College of Physicians
Clinical Guidelines
404 © 2008 American College of Physicians
the American College of Physicians (ACP) recently published
guidelines on screening for men (4).
This guideline presents the available evidence on vari-
ous pharmacologic treatments to prevent fractures in men
and women with low bone density or osteoporosis. Medi-
cations used to treat osteoporosis may affect different parts
of the skeletal system differently, and efficacy for vertebral
fractures does not necessarily imply efficacy for nonverte-
bral fractures. The target audience for this guideline is all
clinicians and the target patient population is all adult men
and women with low bone density or osteoporosis. These
recommendations are based on the systematic evidence re-
view by MacLean and colleagues (5) and the Agency for
Healthcare Research and Quality–sponsored Southern Cal-
ifornia Evidence-Based Practice Center evidence report (6).
The drugs currently approved for prevention of osteo-
porosis include alendronate, ibandronate, risedronate,
zoledronic acid, estrogen, and raloxifene. The drugs cur-
rently approved for treatment of osteoporosis include alen-
dronate, ibandronate, risedronate, calcitonin, teriparatide,
zoledronic acid (in postmenopausal women), and ralox-
ifene. Testosterone, pamidronate, and etidronate are not
approved by the U.S. Food and Drug Administration for
the treatment or prevention of osteoporosis.
METHODS
The literature search done by MacLean and colleagues
for the systematic review (5) included studies from MEDLINE
(1966 to December 2006), the ACP Journal Club database,
the Cochrane Central Register of Controlled Trials (no
date limits), the Cochrane Database of Systematic Reviews
(no date limits), Web sites of the United Kingdom Na-
tional Institute of Health and Clinical Excellence (no date
limits), and the United Kingdom Health Technology As-
sessment Program (January 1998 to December 2006). The
reviewers limited their search to English-language publica-
tions and human studies. They derived evidence for com-
parative benefits of various treatments exclusively from ran-
domized, controlled trials, whereas they included evidence
from other types of studies for short- and long-term harms.
Two physicians independently abstracted data about
study populations, interventions, follow-up, and outcome
ascertainment by using a structured form. For each group
within a randomized trial, a statistician extracted the sam-
ple size and number of persons reporting fractures. Two
reviewers, under the supervision of the statistician, indepen-
dently abstracted information about adverse events. The stat-
istician or the principal investigator resolved disagreements.
This guideline is based on an evaluation of 76 ran-
domized, controlled trials, 4 of which were identified in
the updated search, and 24 meta-analyses that were in-
cluded in the efficacy analyses. The analyses of adverse
events included 491 articles, representing 417 randomized
trials, 25 other controlled clinical trials, 11 open-label trials,
31 large observational studies, and 9 case reports of osteo-
necrosis among bisphosphonate users. MacLean and col-
leagues’ background article (5) includes details about the
methods used for the systematic evidence review.
The ACP rates the evidence and recommendations by
using the Grading of Recommendations, Assessment, De-
velopment, and Evaluation (GRADE) system with minor
modifications (Table 1). In addition, the evidence review-
ers used predefined criteria to assess the quality of system-
atic reviews and randomized trials, based on internal and
external validity assessments detailed in the Quality of Re-
porting of Meta-Analyses (QUOROM) statement (7).
The objective of this guideline is to synthesize the ev-
idence for the following questions:
1. What are the comparative benefits in fracture reduc-
tion among and also within the following treatments for
low bone density: bisphosphonates, specifically alendro-
nate, risedronate, etidronate, ibandronate, pamidronate,
and zoledronic acid; calcitonin; estrogen for women; teripa-
ratide; selective estrogen receptor modulators (SERMs), spe-
cifically raloxifene and tamoxifen; testosterone for men; vita-
mins and minerals, specifically vitamin D and calcium; and
the combination of calcium plus vitamin D?
2. How does fracture reduction resulting from treat-
ments vary among individuals with different risks for frac-
ture as determined by bone mineral density (borderline,
low, or severe), previous fractures (prevention vs. treat-
ment), age, sex, glucocorticoid use, and other factors (such
as community-dwelling vs. institutionalized or vitamin
D–deficient vs. not)?
3. What are the short- and long-term harms (adverse
effects) of these therapies, and do these vary by specific
subpopulations?
COMPARATIVE BENEFITS OF DRUGS VERSUS PLACEBO IN
FRACTURE REDUCTION
Evidence from 24 meta-analyses (8–30) and 35 addi-
tional randomized trials published after the meta-analyses
Table 1. The American College of Physicians’ Guideline
Grading System*
Quality of Evidence Strength of Recommendation
Benefits Clearly
Outweigh Risks
and Burden OR
Risks and Burden
Clearly Outweigh
Benefits
Benefits Finely
Balanced with
Risks and Burden
High Strong Weak
Moderate Strong Weak
Low Strong Weak
Insufficient evidence
to determine net
benefits or risks
I-recommendation
*Adopted from the classification developed by the Grading of Recommendations,
Assessment, Development, and Evaluation (GRADE) workgroup.
Clinical GuidelinesTreatment of Low Bone Density or Osteoporosis to Prevent Fractures
www.annals.org 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 405
(31–65) described the effect of 9 of the 14 agents (alen-
dronate, etidronate, risedronate, calcitonin, estrogen,
teriparatide, raloxifene, calcium, and vitamin D) on frac-
ture incidence. For 4 agents (ibandronate, pamidronate,
zoledronic acid, and tamoxifen), the reviewers found no
meta-analyses and instead gathered the evidence from 14
randomized trials (66–79). No studies were found that
reported fracture rates for testosterone. Three randomized
trials (35, 80, 81) and 1 meta-analysis (82) evaluated the
combination of calcium plus vitamin D on fractures.
Bisphosphonates
Good-quality evidence showed that alendronate, etidro-
nate, ibandronate, and risedronate prevent vertebral frac-
tures. In addition, evidence from good-quality studies
demonstrated that both alendronate and risedronate pre-
vent nonvertebral and hip fractures. Two large randomized
trials showed that zoledronic acid prevents vertebral and
nonvertebral fractures in high-risk populations and reduces
the risk for hip fracture (67, 74). Ibandronate has not been
shown to reduce nonvertebral fractures (68). Of the 6 fairly
small trials that looked at vertebral fractures, 1 demon-
strated a statistically significant reduction in fractures with
pamidronate relative to placebo (0.14 [95% CI, 0.03 to
0.72]) (73). However, after these data were pooled, the
pooled risk estimate for fractures for pamidronate relative
to placebo was not significant (0.52 [CI, 0.21 to 1.24]) (6).
Calcitonin
Fair-quality evidence shows that calcitonin reduces
vertebral fractures (83, 84). Good-quality evidence indi-
cates that calcitonin does not reduce nonvertebral fractures
(13, 16).
Estrogen
Good-quality evidence shows that estrogen reduces the
incidence of vertebral (29, 85), nonvertebral (86), and hip
fractures (85).
Teriparatide
Good-quality evidence shows that teriparatide pre-
vents vertebral fractures. The evidence related to teri-
paratide preventing nonvertebral fractures is mixed; 1 large
randomized trial showed a reduction in nonvertebral frac-
tures (34) but 2 small trials did not (87, 88).
SERMs
Good-quality evidence shows that raloxifene prevents
vertebral fractures, but that tamoxifen has no effect on
vertebral fractures (89–91). In addition, both raloxifene
and tamoxifen had no effect on hip fractures (91). Tamox-
ifen is not approved by the U.S. Food and Drug Admin-
istration for the treatment or prevention of osteoporosis.
Testosterone
No studies reported fracture rates for testosterone.
Calcium and Vitamin D
In the studies evaluated by MacLean and colleagues
(5), the evidence for the effect of calcium alone on reduc-
tion of fractures is complex. Most studies of pharmacologic
agents for osteoporosis include calcium and vitamin D as
part of the treatment regimen. Evidence from 1 meta-
analysis (27) and several randomized trials (35, 48, 51, 92)
showed no significant difference between calcium and pla-
cebo in preventing vertebral, nonvertebral, and hip frac-
tures in postmenopausal women. However, nonadherence
to therapy may influence this result, and 1 trial with a
prespecified analysis of adherent patients found a reduction
in fracture risk (48). A recent meta-analysis (82) concluded
that the relative risk (RR) for fracture with calcium alone
was 0.90 (CI, 0.80 to 1.00), but it did not include a mod-
estly large trial with negative results (35).
MacLean and colleagues (5) included 5 systematic re-
views that evaluated vitamin D. Four meta-analyses (8, 21,
24, 28) found that standard vitamin D (D
2
,D
3
,or25-
hydroxyvitamin [25(OH)]D) did not have any effect on
risk for vertebral, nonvertebral, or hip fractures; a fifth (35)
showed a statistically significant reduction in the pooled
risk for nonvertebral and hip fractures for vitamin D
2
or
D
3
. In addition, MacLean and colleagues identified 3
meta-analyses (21, 23, 24) that showed that vitamin D
analogues [1,25(OH)D and 1(OH)D] significantly re-
duced the risk for vertebral, nonvertebral, and hip frac-
tures. A meta-analysis published after MacLean and col-
leagues’ review concluded that vitamin D and calcium
reduced fractures by 13% (RR, 0.87 [CI, 0.77 to 0.97])
(82).
In summary, for evaluating the comparative benefits of
drugs versus placebo in fracture reduction, good-quality
evidence shows that alendronate, etidronate, ibandronate,
risedronate, calcitonin, teriparatide, and raloxifene prevent
vertebral fractures. The reviewers also found good-quality
evidence that alendronate and risedronate prevent nonver-
tebral and hip fractures. No clear evidence demonstrates
the appropriate duration of treatment with bisphospho-
nates; however, bisphosphonate trials ranged from 3
months to 60 months. Good evidence shows that estrogen
reduced the incidence of vertebral, nonvertebral, and hip
fractures. The effect of calcium alone is less certain. Sys-
tematic reviews of the effectiveness of vitamin D and cal-
cium have reached different conclusions, with the most
recent systematic review (82) finding a modest reduction in
fracture risk.
COMPARATIVE BENEFITS OF DRUGS WITHIN AND
AMONG CLASSES IN FRACTURE REDUCTION
Evidence from 9 randomized trials comparing differ-
ent bisphosphonates (41, 93–100), 1 study comparing dif-
ferent SERMs (101), and 16 studies with head-to-head
comparisons of agents from different classes (31, 32, 35,
37, 42, 50, 64, 98, 100, 102–108) evaluated intermediate
outcomes, such as bone mineral density and changes in
markers of bone turnover. These studies were too short to
detect clinically important differences in fracture incidence.
Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures
406 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 www.annals.org
The 2 head-to-head trials that compared fracture incidence
outcomes (risedronate vs. etidronate [97] and raloxifene vs.
alendronate [107]) were underpowered and showed no statis-
tically significant differences.
In summary, evidence is insufficient to determine
whether one bisphosphonate is superior to another, with
the exception that ibandronate did not reduce nonvertebral
fractures in a relatively large trial (68). Little evidence com-
paring drugs from different classes is available.
BENEFITS OF DRUGS IN DIFFERENT RISK GROUPS FOR
FRACTURE REDUCTION
Low-Risk Populations
We defined “low risk” as a 10-year risk for osteopo-
rotic fracture (vertebral, nonvertebral, or hip) of up to 2%
and a lifetime risk of up to 21%. The reviewers gathered
evidence from 4 meta-analyses (14, 15, 28, 107). Summary
estimates for alendronate showed a statistically nonsignifi-
cant reduction in the risk for vertebral fracture (RR, 0.45
[CI, 0.06 to 3.15]) and nonvertebral fracture (RR, 0.79
[CI, 0.28 to 2.24]) (15). Estrogen did not reduce the risk
for vertebral fracture (28) but reduced nonvertebral frac-
tures (28, 109). However, raloxifene and vitamin D did
reduce the risk for vertebral fractures (raloxifene RR, 0.53
[CI, 0.35 to 0.79]; vitamin D RR, 0.86 [CI, 0.72 to 1.02])
(28). Evidence from 2 randomized trials did not show any
difference between raloxifene and tamoxifen for reducing
fractures (63, 101).
Special Populations
Men
Studies showed that risedronate decreased the risk for
hip fractures (RR, 0.25 [CI, 0.08 to 0.78]) (56), calcitonin
decreased the risk for vertebral fractures (RR, 0.09 [CI,
0.01 to 0.96]) (61), and teriparatide decreased the risk for
total fractures (RR, 0.16 [CI, 0.01 to 0.96]) and possibly
the risk for vertebral fractures (odds ratio [OR], 0.44 [CI,
0.18 to 1.09]) (44). Evidence is insufficient to evaluate the
effect of calcium alone in men (35).
Populations at Increased Risk for Falls
Populations studied included patients with stroke and
hemiplegia, Alzheimer disease, a recent hip fracture, or Par-
kinson disease. Zoledronic acid reduced the risk for verte-
bral fractures (hazard ratio, 0.54 [CI, 0.32 to 0.92]) and
nonvertebral fractures (hazard ratio, 0.73 [CI, 0.55 to
0.98]) in patients with a recent hip fracture (74). In pa-
tients with Alzheimer disease, risedronate reduced the risk
for nonvertebral fracture (RR, 0.29 [CI, 0.15 to 0.57])
(53) and hip fracture (RR, 0.29 [CI, 0.13 to 0.66]) (58).
Risedronate also reduced the risk for hip fracture in pa-
tients with stroke (RR, 0.22 [CI, 0.05 to 0.88]) and hemi-
paresis (RR, 0.25 [CI, 0.08 to 0.78]) (55, 56). In patients
with Parkinson disease, alendronate (RR, 0.30 [CI, 0.12 to
0.78]) reduced the risk for hip fracture (57). Vitamin D
also reduced the risk for hip fracture in patients with stroke
and hemiparesis (RR, 0.12 [CI, 0.02 to 0.90]).
Populations with Renal Insufficiency
One trial (110) showed that alendronate reduced the
risk for fractures to a similar degree in patients with and
those without reduced renal function.
Populations with Long-Term Glucocorticoid Use
Evidence from 3 studies included in a systematic re-
view (111) showed a possible reduction in vertebral frac-
ture rate with bisphosphonate treatment (112–114). Six
additional trials have been published since this systematic
review. Three of these randomized trials (115–117)
showed that bisphosphonates reduced the fracture rate. Re-
sults from 2 studies also showed that risedronate treatment
led to a statistically significant reduction in the absolute
risk (11%) and RR (70%) of incident radiographic verte-
bral fractures after 1 year (117) and in vertebral fractures
(116). In another trial (115), alendronate was associated
with a reduction in the risk for incident radiographic ver-
tebral fractures. However, 3 additional trials showed no
significant effect on fracture risk for etidronate (32, 53),
from calcium (32), between calcium and a combination of
etidronate and calcium (32), or between calcium and pam-
idronate (103).
To summarize the overall fracture reduction benefits
of drug treatments in special populations in different risk
groups, a SERM (raloxifene) and vitamin D both reduced
the risk for vertebral fracture in low-risk patients. Far fewer
men than women have been included in these trials, result-
ing in less evidence about the effectiveness of treatment in
men. In men, risedronate decreased hip fractures and cal-
citonin decreased vertebral fractures. Teriparatide de-
creased total fractures and possibly vertebral fractures. In
patients with a previous hip fracture, zoledronic acid re-
duced the risk for vertebral and nonvertebral fractures.
Risedronate reduced the hip and nonvertebral fracture risk
among patients with Alzheimer disease. Bisphosphonates
(risedronate and alendronate) also reduced the clinical and
radiographic fracture rate in patients receiving glucocorti-
coids.
ADVERSE EFFECTS OF DRUGS
Bisphosphonates
The most common adverse effects of bisphosphonates
are gastrointestinal. Trials reported esophageal ulcerations
from all bisphosphonates except zoledronic acid. One trial
of etidronate versus placebo showed a statistically signifi-
cant increase in esophageal ulceration (OR, 1.33 [CI, 1.05
to 1.68]) (118). Mild upper gastrointestinal events (acid
reflux, esophageal irritation, nausea, vomiting, and heart-
burn) were more common with etidronate in a pooled
analysis (OR, 1.33 [CI, 1.21 to 1.46]) (32, 42, 53, 54, 64,
112, 118–128) and with pamidronate (OR, 3.14 [CI, 1.93
Clinical GuidelinesTreatment of Low Bone Density or Osteoporosis to Prevent Fractures
www.annals.org 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 407
to 5.21]) (75, 79, 129–133). Pooled analysis showed no
difference in occurrence of mild upper gastrointestinal
events between alendronate, ibandronate, risedronate, or
zoledronic acid and placebo. However, pooled analysis of
head-to-head trials showed a higher risk for mild upper
gastrointestinal events with alendronate than with etidr-
onate (OR, 5.89 [CI, 1.61 to 32.7]), calcitonin (OR, 3.42
[CI, 1.79 to 7.00]), or estrogen (OR, 1.57 [CI, 1.00 to
2.46]). The pooled estimate from 3 studies showed that
etidronate users were at increased risk for perforations, ul-
cerations, and gastrointestinal bleeding events (OR, 1.32
[CI, 1.04 to 1.67]) (59, 118, 134), whereas the pooled
estimate from 2 studies showed that ibandronate had a
lower risk for serious gastrointestinal adverse events (OR,
0.33 [CI, 0.14 to 0.74]) (68, 135). Case reports and case
series have documented increased osteonecrosis of the jaw
in patients receiving bisphosphonates, but the most cases of
osteonecrosis have occurred in patients with cancer who
received high doses of intravenous bisphosphonates (136).
However, we could not calculate the risk for this event
from the available studies. Some studies showed a link be-
tween atrial fibrillation and either zoledronic acid or alen-
dronate (5, 137).
Calcitonin
Evidence from randomized trials showed no clinically
important serious adverse events associated with the use of
calcitonin.
Estrogen
Estrogen was associated with an increased risk for
thromboembolic events versus placebo in pooled results
from 4 studies (OR, 1.36 [CI, 1.01 to 1.86]) (37, 85, 138,
139). In addition, pooled results for estrogen–progestin
also showed a higher risk for thromboembolic events versus
placebo (OR, 2.27 [CI, 1.72 to 3.02]) (52, 140, 141).
Pooled odds of stroke were increased with estrogen (OR,
1.28 [CI, 1.05 to 1.57]) (83, 138, 139) and combined
estrogen–progestin (OR, 1.28 [CI, 1.05 to 1.57]) relative
to placebo (52, 140). Women who received estrogen had a
lower pooled risk for breast cancer than those who received
placebo (OR, 0.79 [CI, 0.66 to 0.93]) (83, 138, 142–144).
However, pooled analysis showed that women who re-
ceived an estrogen–progestin combination had an in-
creased risk for breast cancer (OR, 1.28 [CI, 1.03 to 1.60])
(52, 131, 140). One study showed a lower risk for colon
cancer among women who received an estrogen–progestin
combination (OR, 0.64 [CI, 0.43 to 0.95]) (85).
Teriparatide
Evidence from randomized trials showed no clinically
important serious adverse events associated with the use of
teriparatide.
SERMs
Raloxifene increased the pooled risk for pulmonary
embolism (OR, 6.26 [CI, 1.55 to 54.80]) (145, 146). In
addition, pooled results showed that raloxifene increased
the risk for thromboembolic events (OR, 2.08 [CI, 1.47 to
3.02) (145, 147–152) and mild cardiac events, including
chest pain, palpitations, tachycardia, and vasodilatation
(OR, 1.53 [CI, 1.01 to 2.35]) (147, 149, 152–155).
Testosterone
No trials of testosterone reported adverse events; how-
ever, testosterone has well-known side effects.
Calcium and Vitamin D
Evidence from randomized trials showed no clinically
important serious adverse events associated with the use of
calcium and vitamin D.
To summarize the adverse effects of drugs, estrogen
increased the risk for stroke and thromboembolic events;
estrogen–progestin increased the risk for stroke and breast
cancer; and raloxifene increased the risk for pulmonary
embolism, thromboembolic events, and mild cardiac
events. Etidronate was associated with increased risk for
esophageal ulcerations and, in addition to mild upper gas-
trointestinal events, increased the risk for perforations, ul-
cerations, and bleeding events. Alendronate was associated
with a higher risk for mild upper gastrointestinal events
than were etidronate, calcitonin, and estrogen.
SUMMARY
Good evidence shows that bisphosphonates (alendro-
nate, etidronate, and risedronate) reduce the risk for verte-
bral, nonvertebral, and hip fractures. Ibandronate reduces
vertebral fractures. No clear evidence indicates the appro-
priate duration of treatment with bisphosphonates; how-
ever, bisphosphonate trials ranged from 3 months to 60
months. Estrogen reduces the risk for vertebral, nonverte-
bral, and hip fractures. Whereas evidence for fracture risk
reduction from calcium alone is less clear, it is stronger for
vitamin D and calcium in combination (82). Evidence
showed a statistically significant reduction in the risk for
vertebral fractures from vitamin D analogues [1,25(OH)D
and 1(OH)D] but mixed results for nonvertebral and hip
fractures.
Oral bisphosphonates increase the risk for such gastro-
intestinal adverse events as acid reflux. However, pooled
analyses showed no differences in occurrence of mild upper
gastrointestinal events among alendronate, ibandronate,
risedronate, or zoledronic acid versus placebo; however,
pooled analyses of 18 trials of etidronate versus placebo
indicated an increased risk for mild gastrointestinal events.
The evidence linking zoledronic acid infusion with atrial
fibrillation is contradictory. Raloxifene increased the
pooled risk for pulmonary embolism and thromboembolic
events. Estrogen was linked to an increased risk for cere-
brovascular and thromboembolic events.
RECOMMENDATIONS
Recommendation 1: ACP recommends that clinicians offer
pharmacologic treatment to men and women who have known
Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures
408 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 www.annals.org
osteoporosis and to those who have experienced fragility fractures
(Grade: strong recommendation; high-quality evidence).
Good evidence supports the treatment of patients
who have osteoporosis to prevent further loss of bone
and to reduce the risk for initial or subsequent fracture.
Randomized, controlled trials offer good evidence that,
compared with placebo, alendronate, ibandronate,
risedronate, calcitonin, teriparatide, and raloxifene pre-
vent vertebral fractures. Evidence is also good that
teriparatide prevents nonvertebral fractures compared
with placebo and that risedronate and alendronate pre-
vent both nonvertebral and hip fractures compared with
placebo. Estrogen has been shown to be associated with
reduced vertebral, nonvertebral, and hip fractures. The
evidence on use of calcium with or without vitamin D is
mixed, and the effectiveness is modest. Because most
trials of other pharmacologic therapy included their use,
we recommend adding calcium and vitamin D to osteo-
porosis treatment regimens. Evidence is insufficient to deter-
mine the appropriate duration of therapy.
Recommendation 2: ACP recommends that clinicians
consider pharmacologic treatment for men and women who
are at risk for developing osteoporosis (Grade: weak recom-
mendation; moderate-quality evidence).
Evidence supports the treatment of selected patients
who are at risk for osteoporosis but who do not have a
T-score on DXA less than ⫺2.5. Evidence supporting pre-
ventive treatment is stronger for patients who are at mod-
erate risk for osteoporosis, which includes patients who
have a T-score from ⫺1.5 to ⫺2.5, are receiving glucocor-
ticoids, or are older than 62 years of age.
Factors that increase the risk for osteoporosis in
men include age (⬎70 years), low body weight (body
mass index ⬍20 to 25 kg/m
2
), weight loss (⬎10%
[compared with the usual young or adult weight or
weight loss in recent years]), physical inactivity (no
physical activities performed regularly, such as walking,
climbing stairs, carrying weights, housework, or garden-
ing), corticosteroid use, and androgen deprivation ther-
apy (4). Risk factors for women include lower body
weight, the single best predictor of low bone mineral
density; smoking; weight loss; family history; decreased
physical activity; alcohol or caffeine use; and low cal-
cium and vitamin D intake (3). In certain circum-
stances, a single risk factor (for example, androgen de-
privation therapy in men) is enough for clinicians to
consider pharmacologic treatment.
Research groups are developing calculators, such as the
World Health Organization’s Fracture Risk Assessment
Tool (available at www.shef.ac.uk/FRAX/), to predict the
risk for osteoporotic fracture. Such tools will help guide
both clinician and patient decisions.
Recommendation 3: ACP recommends that clinicians
choose among pharmacologic treatment options for osteopo-
rosis in men and women on the basis of an assessment of the
risk and benefits to individual patients (Grade: strong rec-
ommendation; moderate-quality evidence).
We recommend that the choice of therapy for pa-
tients who are candidates for pharmacologic treatment
be guided by judgment of the risks, benefits, and adverse
effects of drug options for each individual patient. Ta-
ble 2 summarizes the benefits and harms of pharmaco-
logic agents for fracture risk. Because good-quality evi-
dence shows that bisphosphonates reduce the risk for
vertebral, nonvertebral, and hip fractures, they are rea-
sonable options to consider as first-line therapy, partic-
ularly for patients who have a high risk for hip fracture.
Evidence from head-to-head trials is insufficient to dem-
onstrate the superiority of one bisphosphonate over an-
other. Alendronate and risedronate have been studied
more than other bisphosphonates (Table 2). Ibandr-
onate has not been shown to reduce nonvertebral or hip
fractures, which may be an important consideration for
some patients. In a recent trial, zoledronic acid admin-
istered to patients with a recent hip fracture reduced
subsequent fracture and improved survival (74). Of the
other agents available for treatment of osteoporosis, es-
trogen has efficacy for vertebral, nonvertebral, and hip
fractures but is associated with other serious risks; cal-
citonin has not been demonstrated to reduce nonverte-
bral and hip fractures; and calcium and vitamin D are
part of the treatment regimen in most studies of phar-
macologic agents for osteoporosis.
Gastrointestinal events are the most common ad-
verse effects associated with bisphosphonate therapy. No
evidence was found that bisphosphonates, calcium, vita-
min D, calcitonin, or teriparatide differ regarding risk
for serious cardiac events. Etidronate is associated with
an increased risk for esophageal ulcers, bleeding events,
and mild upper gastrointestinal events (acid reflux,
esophageal irritation, nausea, vomiting, and heartburn).
Raloxifene is associated with a higher risk for pulmonary
embolism, thromboembolic events, and mild cardiac
events (including chest pain, palpitations, tachycardia,
and vasodilatation). Estrogen is associated with a greater
risk for stroke, and the estrogen–progestin combination
is associated with a greater probability of stroke and
higher odds of breast cancer. In trials, perforations, ul-
cerations, and bleeding events occurred with all of the
bisphosphonates except zoledronic acid.
Recommendation 4: ACP recommends further research to
evaluate treatment of osteoporosis in men and women.
Current evidence is mostly concentrated on post-
menopausal women; more research on other patient pop-
ulations, including men, is needed. Comparative effective-
ness data on preventing fractures from head-to-head
Clinical GuidelinesTreatment of Low Bone Density or Osteoporosis to Prevent Fractures
www.annals.org 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 409
studies with sufficient power to detect differences would be
helpful. The association between bisphosphonates and os-
teonecrosis of the jaw also needs to be studied. Finally,
further research is needed on prevention strategies in both
men and women and on the appropriate duration of treat-
ment for osteoporosis.
Table 2. Summary of Evidence about Drugs and Fracture Risk
Agent Effect on Risk and Level of Evidence Adverse Effects FDA Approval
Vertebral Fracture Nonvertebral
Fracture
Hip Fracture
Bisphosphonates
Alendronate 2; strong evidence 2; strong evidence 2; strong evidence Mild upper GI events,
esophageal
ulcerations,
perforations, and
bleeding events
Prevention or
treatment
Etidronate 2; strong evidence 7; fair evidence 7; strong evidence Mild upper GI events,
esophageal
ulcerations,
perforations, and
bleeding events
Not FDA-approved for
prevention or
treatment
Ibandronate 2; strong evidence 7; strong evidence Not studied Esophageal
ulcerations,
perforations, and
bleeding events
Prevention or
treatment
Pamidronate 7; weak evidence 7; weak evidence 7; weak evidence Mild upper GI events,
esophageal
ulcerations,
perforations, and
bleeding events
Not FDA-approved for
prevention or
treatment
Risedronate 2; strong evidence 2; strong evidence 2; strong evidence Esophageal
ulcerations,
perforations, and
bleeding events
Prevention or
treatment
Zoledronic
acid
2; strong evidence 2; strong evidence 2; strong evidence Muscular and joint
pain
Prevention
Calcitonin 2; fair evidence 7; strong evidence Not studied No clinically significant
adverse effects
Treatment
Estrogen 2; strong evidence 2; strong evidence 2; strong evidence Thromboembolic
events;
cerebrovascular
accident, stroke,
and breast cancer
(when combined
with progestin);
gynecologic
problems
(endometrial
bleeding); breast
abnormalities (pain,
tenderness, and
fibrocytosis)
Prevention
Teriparatide 2; strong evidence 2; fair evidence 7; weak evidence No clinically significant
adverse effects
Treatment
SERMs
Raloxifene 2; strong evidence 7; strong evidence 7; strong evidence Pulmonary embolism,
thromboembolic
events
Prevention or
treatment
Tamoxifen 7; strong evidence Not studied 7; strong evidence Pulmonary embolism Not FDA-approved for
prevention or
treatment
Testosterone Not studied Not studied Not studied No clinically significant
adverse effects
Not FDA-approved for
prevention or
treatment
Calcium and
vitamin D
Modest effect*;
strong evidence
Modest effect*;
strong evidence
Modest effect*;
strong evidence
No clinically significant
adverse effects
Over the counter
2⫽decreased; 7⫽no effect; FDA ⫽U.S. Food and Drug Administration; GI ⫽gastrointestinal; SERM ⫽selective estrogen receptor modulator.
*Pooled estimate across fracture sites.
Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures
410 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 www.annals.org
From the American College of Physicians and University of Pennsylva-
nia, Philadelphia, Pennsylvania; Veterans Affairs Greater Los Angeles
Healthcare System and RAND, Santa Monica, California; University of
Arkansas, Little Rock, Arkansas; and Veterans Affairs Palo Alto Health
Care System and Stanford University, Stanford, California.
Note: Clinical practice guidelines are “guides” only and may not apply to
all patients and all clinical situations. Thus, they are not intended to
override clinicians’ judgment. All ACP clinical practice guidelines are
considered automatically withdrawn or invalid 5 years after publication,
or once an update has been issued.
Disclaimer: The authors of this article are responsible for its contents,
including any clinical or treatment recommendations. No statement in
this article should be construed as an official position of the Agency for
Healthcare Research and Quality or the U.S. Department of Health and
Human Services.
Grant Support: Financial support for the development of this guideline
comes exclusively from the American College of Physicians’ operating
budget.
Potential Financial Conflicts of Interest: Employment: R. Hopkins
(University of Arkansas). Consultancies: D.K. Owens (GE Healthcare).
Grants received: V. Snow (Novo Nordisk, United Healthcare Founda-
tion, Centers for Disease Control and Prevention, Atlantic Philanthro-
pies). Any conflict of interest of the Guideline Development Committee
group members was declared, discussed, and resolved.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, Amer-
ican College of Physicians, 190 N. Independence Mall West, Philadel-
phia, PA 19106; e-mail, aqaseem@acponline.org.
Current author addresses are available at www.annals.org.
References
1. NIH Consensus Development Program. Osteoporosis Prevention, Diagnosis,
and Therapy. Bethesda, MD: National Institutes of Health; 2000. Accessed at
http://consensus.nih.gov/2000/2000Osteoporosis111html.htm on 31 July 2008.
2. WHO scientific group on the assessment of osteoporosis at primary health care
level. Geneva: World Health Organization; 2007.
3. U.S. Preventive Services Task Force. Screening for Osteoporosis in Postmeno-
pausal Women: Recommendations and Rationale. Rockville, MD: Agency for
Healthcare Research and Quality; 2002. Accessed at www.ahrq.gov/clinic
/3rduspstf/osteoporosis/osteorr.htm on 31 July 2008.
4. Qaseem A, Snow V, Shekelle P, Hopkins R, Forciea MA, Owens D. Clinical
Efficacy Assessment Subcommittee of the American College of Physicians.
Screening for osteoporosis in men: a clinical practice guideline from the American
College of Physicians. Ann Intern Med. 2008;148:680-4. [PMID: 18458281]
5. MacLean C, Newberry S, Maglione M, McMahon M, Ranganath V, Sut-
torp M, et al. Systematic review: comparative effectiveness of treatments to pre-
vent fractures in men and women with low bone density or osteoporosis. Ann
Intern Med. 2008;148:197-213. [PMID: 18087050]
6. MacLean C, Alexander A, Carter J, Chen S, Desai SB, Grossman J, et al.
Comparative Effectiveness of Treatments to Prevent Fractures in Men and
Women with Low Bone Density or Osteoporosis. Comparative Effectiveness
Review no. 12. (Prepared by the Southern California/RAND Evidence-based
Practice Center under contract 290-02-0003). Rockville, MD: Agency for
Healthcare Research and Quality; December 2007. Accessed at www.effective
healthcare.ahrq.gov/reports/final.cfm on 31 July 2008.
7. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving
the quality of reports of meta-analyses of randomised controlled trials: the
QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;
354:1896-900. [PMID: 10584742]
8. Avenell A, Gillespie WJ, Gillespie LD, O’Connell DL. Vitamin D and vita-
min D analogues for preventing fractures associated with involutional and post-
menopausal osteoporosis. Cochrane Database Syst Rev. 2005:CD000227.
[PMID: 16034849]
9. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T,
Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a
meta-analysis of randomized controlled trials. JAMA. 2005;293:2257-64.
[PMID: 15886381]
10. Boonen S, Laan RF, Barton IP, Watts NB. Effect of osteoporosis treatments
on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat
studies. Osteoporos Int. 2005;16:1291-8. [PMID: 15986101]
11. Cranney A, Welch V, Adachi JD, Homik J, Shea B, Suarez-Almazor ME,
et al. Calcitonin for the treatment and prevention of corticosteroid-induced os-
teoporosis. Cochrane Database Syst Rev. 2000:CD001983. [PMID: 10796457]
12. Cranney A, Tugwell P, Adachi J, Weaver B, Zytaruk N, Papaioannou A,
et al. Osteoporosis Methodology Group and The Osteoporosis Research Advi-
sory Group. Meta-analyses of therapies for postmenopausal osteoporosis. III.
Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis.
Endocr Rev. 2002;23:517-23. [PMID: 12202466]
13. Cranney A, Tugwell P, Zytaruk N, Robinson V, Weaver B, Shea B, et al.
Osteoporosis Methodology Group and The Osteoporosis Research Advisory
Group. Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-
analysis of calcitonin for the treatment of postmenopausal osteoporosis. Endocr
Rev. 2002;23:540-51. [PMID: 12202469]
14. Cranney A, Adachi JD, Griffith L, Guyatt G, Krolicki N, Robinson VA,
et al. WITHDRAWN: Etidronate for treating and preventing postmenopausal
osteoporosis. Cochrane Database Syst Rev. 2006:CD003376. [PMID:
17636719]
15. Cranney A, Wells G, Willan A, Griffith L, Zytaruk N, Robinson V, et al.
Osteoporosis Methodology Group and The Osteoporosis Research Advisory
Group. Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-
analysis of alendronate for the treatment of postmenopausal women. Endocr Rev.
2002;23:508-16. [PMID: 12202465]
16. Kanis JA, McCloskey EV. Effect of calcitonin on vertebral and other frac-
tures. QJM. 1999;92:143-9. [PMID: 10326073]
17. Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S,
et al. Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alen-
dronate Osteoporosis Treatment Study Groups. JAMA. 1997;277:1159-64.
[PMID: 9087473]
18. Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety
and efficacy of risedronate in patients with age-related reduced renal function as
estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical
trials. J Bone Miner Res. 2005;20:2105-15. [PMID: 16294264]
19. Nguyen ND, Eisman JA, Nguyen TV. Anti-hip fracture efficacy of biophos-
phonates: a Bayesian analysis of clinical trials. J Bone Miner Res. 2006;21:340-9.
[PMID: 16526127]
20. Palmer S, McGregor DO, Strippoli GF. Interventions for preventing bone
disease in kidney transplant recipients. Cochrane Database Syst Rev. 2005:
CD005015. [PMID: 15846740]
21. Papadimitropoulos E, Wells G, Shea B, Gillespie W, Weaver B, et al.
Osteoporosis Methodology Group and The Osteoporosis Research Advisory
Group. Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-
analysis of the efficacy of vitamin D treatment in preventing osteoporosis in
postmenopausal women. Endocr Rev. 2002;23:560-9. [PMID: 12202471]
22. Papapoulos SE, Quandt SA, Liberman UA, Hochberg MC, Thompson
DE. Meta-analysis of the efficacy of alendronate for the prevention of hip frac-
tures in postmenopausal women. Osteoporos Int. 2005;16:468-74. [PMID:
15448985]
23. Richy F, Ethgen O, Bruyere O, Reginster JY. Efficacy of alphacalcidol and
calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis of
their effects on bone mineral density and fracture rate. Osteoporos Int. 2004;15:
301-10. [PMID: 14740153]
24. Richy F, Schacht E, Bruyere O, Ethgen O, Gourlay M, Reginster JY.
Vitamin D analogs versus native vitamin D in preventing bone loss and osteo-
porosis-related fractures: a comparative meta-analysis. Calcif Tissue Int. 2005;76:
176-86. [PMID: 15692726]
25. Sawka AM, Papaioannou A, Adachi JD, Gafni A, Hanley DA, Thabane L.
Does alendronate reduce the risk of fracture in men? A meta-analysis incorporat-
ing prior knowledge of anti-fracture efficacy in women. BMC Musculoskelet
Disord. 2005;6:39. [PMID: 16008835]
Clinical GuidelinesTreatment of Low Bone Density or Osteoporosis to Prevent Fractures
www.annals.org 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 411
26. Seeman E, Crans GG, Diez-Perez A, Pinette KV, Delmas PD. Anti-verte-
bral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int. 2006;17:
313-6. [PMID: 16217588]
27. Shea B, Wells G, Cranney A, Zytaruk N, Robinson V, Griffith L, et al.
Osteoporosis Methodology Group and The Osteoporosis Research Advisory
Group. Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-
analysis of calcium supplementation for the prevention of postmenopausal osteo-
porosis. Endocr Rev. 2002;23:552-9. [PMID: 12202470]
28. Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley J. A
systematic review and economic evaluation of alendronate, etidronate, rise-
dronate, raloxifene and teriparatide for the prevention and treatment of post-
menopausal osteoporosis. Health Technol Assess. 2005;9:1-160. [PMID:
15929857]
29. Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention
of vertebral fractures: a meta-analysis of randomised trials. BMC Musculoskelet
Disord. 2001;2:7. [PMID: 11716794]
30. Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N, et al.
Osteoporosis Methodology Group and The Osteoporosis Research Advisory
Group. Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-
analysis of the efficacy of hormone replacement therapy in treating and prevent-
ing osteoporosis in postmenopausal women. Endocr Rev. 2002;23:529-39.
[PMID: 12202468]
31. Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW,
et al. Alendronate and estrogen effects in postmenopausal women with low bone
mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab.
2000;85:720-6. [PMID: 10690882]
32. Campbell IA, Douglas JG, Francis RM, Prescott RJ, Reid DM. Research
Committee of the British Thoracic Society. Five year study of etidronate and/or
calcium as prevention and treatment for osteoporosis and fractures in patients
with asthma receiving long term oral and/or inhaled glucocorticoids. Thorax.
2004;59:761-8. [PMID: 15333852]
33. Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ,
et al. Women’s Health Initiative Investigators. Effects of estrogen plus progestin
on risk of fracture and bone mineral density: the Women’s Health Initiative
randomized trial. JAMA. 2003;290:1729-38. [PMID: 14519707]
34. Gallagher JC, Genant HK, Crans GG, Vargas SJ, Krege JH. Teripa-
ratide reduces the fracture risk associated with increasing number and
severity of osteoporotic fractures. J Clin Endocrinol Metab. 2005;90:
1583-7. [PMID: 15613428]
35. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS,
McPherson GC, et al. RECORD Trial Group. Oral vitamin D3 and calcium
for secondary prevention of low-trauma fractures in elderly people (Randomised
Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-con-
trolled trial. Lancet. 2005;365:1621-8. [PMID: 15885294]
36. Greenspan SL, Bhattacharya RK, Sereika SM, Brufsky A, Vogel VG. Pre-
vention of bone loss in survivors of breast cancer: A randomized, double-blind,
placebo-controlled clinical trial. J Clin Endocrinol Metab. 2007;92:131-6.
[PMID: 17047022]
37. Greenspan SL, Resnick NM, Parker RA. Combination therapy with hor-
mone replacement and alendronate for prevention of bone loss in elderly women:
a randomized controlled trial. JAMA. 2003;289:2525-33. [PMID: 12759324]
38. Hay JE, Malinchoc M, Dickson ER. A controlled trial of calcitonin therapy
for the prevention of post-liver transplantation atraumatic fractures in patients
with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2001;
34:292-8. [PMID: 11281559]
39. Homik J, Cranney A, Shea B, Tugwell P, Wells G, Adachi R, et al. Bisphos-
phonates for steroid induced osteoporosis. Cochrane Database Syst Rev. 2000:
CD001347. [PMID: 10796432]
40. Hooper MJ, Ebeling PR, Roberts AP, Graham JJ, Nicholson GC,
D’Emden M, et al. Risedronate prevents bone loss in early postmenopausal
women: a prospective randomized, placebo-controlled trial. Climacteric. 2005;8:
251-62. [PMID: 16390757]
41. Hosking D, Adami S, Felsenberg D, Andia JC, Va¨lima¨ki M, Benhamou L,
et al. Comparison of change in bone resorption and bone mineral density with
once-weekly alendronate and daily risedronate: a randomised, placebo-controlled
study. Curr Med Res Opin. 2003;19:383-94. [PMID: 13678475]
42. Ishida Y, Kawai S. Comparative efficacy of hormone replacement therapy,
etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women
with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am J Med.
2004;117:549-55. [PMID: 15465502]
43. Kanaji A, Higashi M, Namisato M, Nishio M, Ando K, Yamada H. Effects
of risedronate on lumbar bone mineral density, bone resorption, and incidence of
vertebral fracture in elderly male patients with leprosy. Lepr Rev. 2006;77:147-
53. [PMID: 16895071]
44. Kaufman JM, Orwoll E, Goemaere S, San Martin J, Hossain A, Dalsky
GP, et al. Teriparatide effects on vertebral fractures and bone mineral density in
men with osteoporosis: treatment and discontinuation of therapy. Osteoporos
Int. 2005;16:510-6. [PMID: 15322742]
45. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC,
Moffett AH, et al. AMG 162 Bone Loss Study Group. Denosumab in post-
menopausal women with low bone mineral density. N Engl J Med. 2006;354:
821-31. [PMID: 16495394]
46. Milgrom C, Finestone A, Novack V, Pereg D, Goldich Y, Kreiss Y, et al.
The effect of prophylactic treatment with risedronate on stress fracture incidence
among infantry recruits. Bone. 2004;35:418-24. [PMID: 15268892]
47. Palomba S, Orio F Jr, Manguso F, Falbo A, Russo T, Tolino A, et al.
Efficacy of risedronate administration in osteoporotic postmenopausal women
affected by inflammatory bowel disease. Osteoporos Int. 2005;16:1141-9.
[PMID: 15928801]
48. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplemen-
tation on clinical fracture and bone structure: results of a 5-year, double-blind,
placebo-controlled trial in elderly women. Arch Intern Med. 2006;166:869-75.
[PMID: 16636212]
49. Fracture Intervention Trial Research Group. Effect of alendronate on ver-
tebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at
the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005;80:
343-9. [PMID: 15757015]
50. Reid IR, Eastell R, Fogelman I, Adachi JD, Rosen A, Netelenbos C, et al.
A comparison of the effects of raloxifene and conjugated equine estrogen on bone
and lipids in healthy postmenopausal women. Arch Intern Med.
2004;164:871-9. [PMID: 15111373]
51. Reid IR, Mason B, Horne A, Ames R, Reid HE, Bava U, et al. Randomized
controlled trial of calcium in healthy older women. Am J Med. 2006;119:777-85.
[PMID: 16945613]
52. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C,
Stefanick ML, et al. Writing Group for the Women’s Health Initiative Inves-
tigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal
women: principal results From the Women’s Health Initiative randomized con-
trolled trial. JAMA. 2002;288:321-33. [PMID: 12117397]
53. Sato S, Ohosone Y, Suwa A, Yasuoka H, Nojima T, Fujii T, et al. Effect of
intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis in
Japanese patients with connective tissue disease: 3 year followup. J Rheumatol.
2003;30:2673-9. [PMID: 14719212]
54. Sato Y, Honda Y, Iwamoto J. Etidronate for fracture prevention in amyo-
trophic lateral sclerosis: a randomized controlled trial. Bone. 2006;39:1080-6.
[PMID: 16777503]
55. Sato Y, Iwamoto J, Kanoko T, Satoh K. Risedronate therapy for prevention
of hip fracture after stroke in elderly women. Neurology. 2005;64:811-6.
[PMID: 15753414]
56. Sato Y, Iwamoto J, Kanoko T, Satoh K. Risedronate sodium therapy for
prevention of hip fracture in men 65 years or older after stroke. Arch Intern Med.
2005;165:1743-8. [PMID: 16087822]
57. Sato Y, Iwamoto J, Kanoko T, Satoh K. Alendronate and vitamin D2 for
prevention of hip fracture in Parkinson’s disease: a randomized controlled trial.
Mov Disord. 2006;21:924-9. [PMID: 16538619]
58. Sato Y, Kanoko T, Satoh K, Iwamoto J. The prevention of hip fracture with
risedronate and ergocalciferol plus calcium supplementation in elderly women
with Alzheimer disease: a randomized controlled trial. Arch Intern Med. 2005;
165:1737-42. [PMID: 16087821]
59. Sato Y, Kanoko T, Yasuda H, Satoh K, Iwamoto J. Beneficial effect of
etidronate therapy in immobilized hip fracture patients. Am J Phys Med Rehabil.
2004;83:298-303. [PMID: 15024332]
60. Sorensen OH, Crawford GM, Mulder H, Hosking DJ, Gennari C, Mell-
strom D, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled
clinical experience. Bone. 2003;32:120-6. [PMID: 12633783]
61. To´th E, Csupor E, Me´sza´ros S, Ferencz V, Ne´meth L, McCloskey EV, et al.
The effect of intranasal salmon calcitonin therapy on bone mineral density in
idiopathic male osteoporosis without vertebral fractures—an open label study.
Bone. 2005;36:47-51. [PMID: 15664001]
62. Trovas GP, Lyritis GP, Galanos A, Raptou P, Constantelou E. A random-
Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures
412 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 www.annals.org
ized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis:
effects on bone mineral density and bone markers. J Bone Miner Res. 2002;17:
521-7. [PMID: 11874243]
63. Ushiroyama T, Ikeda A, Sakai M, Higashiyama T, Ueki M. Effects of the
combined use of calcitonin and 1
␣
-hydroxycholecalciferol on vertebral bone loss
and bone turnover in women with postmenopausal osteopenia and osteoporosis:
a prospective study of long-term and continuous administration with low dose
calcitonin. Maturitas. 2001;40:229-38. [PMID: 11731184]
64. Wimalawansa SJ. A four-year randomized controlled trial of hormone re-
placement and bisphosphonate, alone or in combination, in women with post-
menopausal osteoporosis. Am J Med. 1998;104:219-26. [PMID: 9552083]
65. Zein CO, Jorgensen RA, Clarke B, Wenger DE, Keach JC, Angulo P, et al.
Alendronate improves bone mineral density in primary biliary cirrhosis: a
randomized placebo-controlled trial. Hepatology. 2005;42:762-71.
[PMID: 16175618]
66. Aris RM, Lester GE, Renner JB, Winders A, Denene Blackwood A, Lark
RK, et al. Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis
following lung transplantation. Am J Respir Crit Care Med. 2000;162:941-6.
[PMID: 10988110]
67. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al.
HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of
postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-22. [PMID:
17476007]
68. Chesnut III CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth
A, et al. Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North
America and Europe (BONE). Effects of oral ibandronate administered daily or
intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res.
2004;19:1241-9. [PMID: 15231010]
69. Coco M, Glicklich D, Faugere MC, Burris L, Bognar I, Durkin P, et al.
Prevention of bone loss in renal transplant recipients: a prospective, randomized
trial of intravenous pamidronate. J Am Soc Nephrol. 2003;14:2669-76. [PMID:
14514747]
70. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M,
Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the
National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer
Inst. 1998;90:1371-88. [PMID: 9747868]
71. Grotz W, Nagel C, Poeschel D, Cybulla M, Petersen KG, Uhl M, et al.
Effect of ibandronate on bone loss and renal function after kidney transplanta-
tion. J Am Soc Nephrol. 2001;12:1530-7. [PMID: 11423583]
72. Kananen K, Volin L, Laitinen K, Alfthan H, Ruutu T, Va¨lima¨ki MJ.
Prevention of bone loss after allogeneic stem cell transplantation by calcium,
vitamin D, and sex hormone replacement with or without pamidronate. J Clin
Endocrinol Metab. 2005;90:3877-85. [PMID: 15797959]
73. Kim SH, Lim SK, Hahn JS. Effect of pamidronate on new vertebral fractures
and bone mineral density in patients with malignant lymphoma receiving che-
motherapy. Am J Med. 2004;116:524-8. [PMID: 15063813]
74. Lyles KW, Colo´n-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mau-
talen C, et al. HORIZON Recurrent Fracture Trial. Zoledronic acid and clin-
ical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-809.
[PMID: 17878149]
75. Ninkovic M, Love S, Tom BD, Bearcroft PW, Alexander GJ, Compston
JE. Lack of effect of intravenous pamidronate on fracture incidence and bone
mineral density after orthotopic liver transplantation. J Hepatol. 2002;37:93-100.
[PMID: 12076867]
76. Ravn P, Clemmesen B, Riis BJ, Christiansen C. The effect on bone mass
and bone markers of different doses of ibandronate: a new bisphosphonate for
prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized,
double-blind, placebo-controlled dose-finding study. Bone. 1996;19:527-33.
[PMID: 8922653]
77. Recker R, Stakkestad JA, Chesnut CH 3rd, Christiansen C, Skag A, Hois-
eth A, et al. Insufficiently dosed intravenous ibandronate injections are associated
with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone.
2004;34:890-9. [PMID: 15121021]
78. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U,
et al. Intravenous zoledronic acid in postmenopausal women with low bone
mineral density. N Engl J Med. 2002;346:653-61. [PMID: 11870242]
79. Reid IR, Wattie DJ, Evans MC, Gamble GD, Stapleton JP, Cornish J.
Continuous therapy with pamidronate, a potent bisphosphonate, in postmeno-
pausal osteoporosis. J Clin Endocrinol Metab. 1994;79:1595-9. [PMID:
7989461]
80. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al.
Women’s Health Initiative Investigators. Calcium plus vitamin D supplemen-
tation and the risk of fractures. N Engl J Med. 2006;354:669-83. [PMID:
16481635]
81. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al.
Randomised controlled trial of calcium and supplementation with cholecalciferol
(vitamin D3) for prevention of fractures in primary care. BMJ. 2005;330:1003.
[PMID: 15860827]
82. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium
or calcium in combination with vitamin D supplementation to prevent fractures
and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007;
370:657-66. [PMID: 17720017]
83. Ishida Y, Kawai S. Comparative efficacy of hormone replacement therapy,
etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women
with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am J Med.
2004;117:549-55. [PMID: 15465502]
84. To´th E, Csupor E, Me´sza´ros S, Ferencz V, Ne´meth L, McCloskey EV, et al.
The effect of intranasal salmon calcitonin therapy on bone mineral density in
idiopathic male osteoporosis without vertebral fractures—an open label study.
Bone. 2005;36:47-51. [PMID: 15664001]
85. Women’s Health Initiative Steering Committee. Effects of conjugated
equine estrogen in postmenopausal women with hysterectomy: the Women’s
Health Initiative randomized controlled trial. JAMA. 2004;291:1701-12.
[PMID: 15082697]
86. Homik JE, Cranney A, Shea B, Tugwell P, Wells G, Adachi JD, et al.
A meta-analysis on the use of bisphosphonates in corticosteroid induced osteo-
porosis. J Rheumatol. 1999;26:1148-57. [PMID: 10332982]
87. Kaufman JM, Orwoll E, Goemaere S, San Martin J, Hossain A, Dalsky
GP, et al. Teriparatide effects on vertebral fractures and bone mineral density in
men with osteoporosis: treatment and discontinuation of therapy. Osteoporos
Int. 2005;16:510-6. [PMID: 15322742]
88. Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A, et al.
The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone
density in men with osteoporosis. J Bone Miner Res. 2003;18:9-17. [PMID:
12510800]
89. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T,
Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women
with osteoporosis treated with raloxifene: results from a 3-year randomized clin-
ical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.
JAMA. 1999;282:637-45. [PMID: 10517716]
90. Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knicker-
bocker RK, et al. Treatment of established postmenopausal osteoporosis with
raloxifene: a randomized trial. J. Bone Miner Res. 1998;13:1747-54. [PMID:
9797484]
91. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M,
Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the
National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl. Cancer
Inst. 1998;90:1371-88. [PMID: 9747868]
92. Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B,
et al. Preventing fractures among older people living in institutional care: a prag-
matic randomised double blind placebo controlled trial of vitamin D supplemen-
tation. Osteoporos Int. 2007;18:811-8. [PMID: 17473911]
93. Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SM,
et al. Comparison of weekly treatment of postmenopausal osteoporosis with alen-
dronate versus risedronate over two years. J Clin Endocrinol Metab. 2006;91:
2631-7. [PMID: 16636120]
94. Fukunaga M, Kushida K, Kishimoto H, Shiraki M, Taketani Y, Minaguchi
H, et al. Risedronate Phase III Research Group. A comparison of the effect of
risedronate and etidronate on lumbar bone mineral density in Japanese patients
with osteoporosis: a randomized controlled trial. Osteoporos Int. 2002;13:971-9.
[PMID: 12459940]
95. Guan˜abens N, Pare´s A, Ros I, Alvarez L, Pons F, Caballerı´a L, et al.
Alendronate is more effective than etidronate for increasing bone mass in os-
teopenic patients with primary biliary cirrhosis. Am J Gastroenterol. 2003;98:
2268-74. [PMID: 14572578]
96. Iwamoto J, Takeda T, Ichimura S, Uzawa M. Comparative effects of treat-
ment with etidronate and alendronate on bone resorption, back pain, and activ-
ities of daily living in elderly women with vertebral fractures. Keio J Med. 2003;
52:230-5. [PMID: 14748475]
97. Kushida K, Fukunaga M, Kishimoto H, Shiraki M, Itabashi A, Inoue T,
Clinical GuidelinesTreatment of Low Bone Density or Osteoporosis to Prevent Fractures
www.annals.org 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 413
et al. A comparison of incidences of vertebral fracture in Japanese patients with
involutional osteoporosis treated with risedronate and etidronate: a randomized,
double-masked trial. J Bone Miner Metab. 2004;22:469-78. [PMID: 15316868]
98. Muscoso E, Puglisi N, Mamazza C, Lo Giudice F, Testai M, Abbate S,
et al. Antiresorption therapy and reduction in fracture susceptibility in the osteo-
porotic elderly patient: open study. Eur Rev Med Pharmacol Sci. 2004;8:97-102.
[PMID: 15267123]
99. Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S,
et al. Fosamax Actonel Comparison Trial Investigators. Treatment with once-
weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in
women with postmenopausal osteoporosis: a randomized double-blind study. J
Bone Miner Res. 2005;20:141-51. [PMID: 15619680]
100. Tauchmanova` L, De Simone G, Musella T, Orio F, Ricci P, Nappi C, et
al. Effects of various antireabsorptive treatments on bone mineral density in hy-
pogonadal young women after allogeneic stem cell transplantation. Bone Marrow
Transplant. 2006;37:81-8. [PMID: 16247420]
101. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS,
Atkins JN, et al. National Surgical Adjuvant Breast and Bowel Project
(NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive
breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and
Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-41. [PMID: 16754727]
102. Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz A, et
al. A randomized double-blind trial to compare the efficacy of teriparatide [re-
combinant human parathyroid hormone (1-34)] with alendronate in postmeno-
pausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87:4528-35.
[PMID: 12364430]
103. Boutsen Y, Jamart J, Esselinckx W, Stoffel M, Devogelaer JP. Primary
prevention of glucocorticoid-induced osteoporosis with intermittent intravenous
pamidronate: a randomized trial. Calcif Tissue Int. 1997;61:266-71. [PMID:
9312195]
104. Garcia-Delgado I, Prieto S, Gil-Fraguas L, Robles E, Rufilanchas JJ,
Hawkins F. Calcitonin, etidronate, and calcidiol treatment in bone loss after
cardiac transplantation. Calcif Tissue Int. 1997;60:155-9. [PMID: 9056163]
105. Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich R, Ross P,
et al. Prevention of bone loss with alendronate in postmenopausal women under
60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl
J Med. 1998;338:485-92. [PMID: 9443925]
106. Luckey M, Kagan R, Greenspan S, Bone H, Kiel RD, Simon J, et al.
Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of
postmenopausal osteoporosis. Menopause. 2004;11:405-15. [PMID: 15243278]
107. Recker RR, Kendler D, Recknor CP, Rooney TW, Lewiecki EM, Utian
WH, et al. Comparative effects of raloxifene and alendronate on fracture out-
comes in postmenopausal women with low bone mass. Bone. 2007;40:843-51.
[PMID: 17182297]
108. Uchida S, Taniguchi T, Shimizu T, Kakikawa T, Okuyama K, Okaniwa
M, et al. Therapeutic effects of alendronate 35 mg once weekly and 5 mg once
daily in Japanese patients with osteoporosis: a double-blind, randomized study. J
Bone Miner Metab. 2005;23:382-8. [PMID: 16133688]
109. Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention
of nonvertebral fractures: a meta-analysis of randomized trials. JAMA. 2001;285:
2891-7. [PMID: 11401611]
110. Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A, et al.
Alendronate treatment in women with normal to severely impaired renal func-
tion: an analysis of the fracture intervention trial. J Bone Miner Res. 2007;22:
503-8. [PMID: 17243862]
111. Blair MM, Carson DS, Barrington R. Bisphosphonates in the prevention
and treatment of glucocorticoid-induced osteoporosis. J Fam Pract. 2000;49:839-
48. [PMID: 11032210]
112. Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R, et al.
Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N
Engl J Med. 1997;337:382-7. [PMID: 9241127]
113. Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M, et al.
Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month,
multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Arthritis Rheum. 1999;42:2309-18. [PMID: 10555025]
114. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S,
et al. Alendronate for the prevention and treatment of glucocorticoid-induced
osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N
Engl J Med. 1998;339:292-9. [PMID: 9682041]
115. Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E,
et al. Two-year effects of alendronate on bone mineral density and vertebral
fracture in patients receiving glucocorticoids: a randomized, double-blind, place-
bo-controlled extension trial. Arthritis Rheum. 2001;44:202-11. [PMID:
11212161]
116. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH,
Adami S, et al. Efficacy and safety of daily risedronate in the treatment of corti-
costeroid-induced osteoporosis in men and women: a randomized trial. European
Corticosteroid-Induced Osteoporosis Treatment Study. J Bone Miner Res. 2000;
15:1006-13. [PMID: 10841169]
117. Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF, et al.
Effects of risedronate treatment on bone density and vertebral fracture in patients
on corticosteroid therapy. Calcif Tissue Int. 2000;67:277-85. [PMID:
11000340]
118. van Staa T, Abenhaim L, Cooper C. Upper gastrointestinal adverse events
and cyclical etidronate. Am J Med. 1997;103:462-7. [PMID: 9428828]
119. Adami S, Bruni V, Bianchini D, Becorpi A, Lombardi P, Campagnoli C,
et al. Prevention of early postmenopausal bone loss with cyclical etidronate. J
Endocrinol Invest. 2000;23:310-6. [PMID: 10882149]
120. Cortet B, Hachulla E, Barton I, Bonvoisin B, Roux C. Evaluation of the
efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in
patients with inflammatory rheumatic diseases. A randomized study. Rev Rhum
Engl Ed. 1999;66:214-9. [PMID: 10339777]
121. Geusens P, Dequeker J, Vanhoof J, Stalmans R, Boonen S, Joly J,
et al. Cyclical etidronate increases bone density in the spine and hip of
postmenopausal women receiving long term corticosteroid treatment. A
double blind, randomised placebo controlled study. Ann Rheum Dis.
1998;57:724-7. [PMID: 10070271]
122. Geusens P, Vanhoof J, Joly J, Dequeker J, Nijs J, Rauss J. Cyclic etidronate
increases bone density in the spine and hip in postmenopausal women on chronic
corticosteroid treatment. A double-blind controlled study. . Bone. 1997;20:9S.
123. Heath DA, Bullivant BG, Boiven C, Balena R. The effects of cyclical
etidronate on early postmenopausal bone loss: an open, randomized controlled
study. J Clin Densitom. 2000;3:27-33. [PMID: 10745299]
124. Herd RJ, Balena R, Blake GM, Ryan PJ, Fogelman I. The prevention of
early postmenopausal bone loss by cyclical etidronate therapy: a 2-year, double-
blind, placebo-controlled study. Am J Med. 1997;103:92-9. [PMID: 9274891]
125. Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Delmas PD, Balena
R. Prevention of early postmenopausal bone loss with cyclical etidronate therapy
(a double-blind, placebo-controlled study and 1-year follow-up). J Clin Endocri-
nol Metab. 1997;82:2784-91. [PMID: 9284696]
126. Pitt P, Li F, Todd P, Webber D, Pack S, Moniz C. A double blind placebo
controlled study to determine the effects of intermittent cyclical etidronate on
bone mineral density in patients on long-term oral corticosteroid treatment. Tho-
rax. 1998;53:351-6. [PMID: 9708225]
127. Roux C, Oriente P, Laan R, Hughes RA, Ittner J, Goemaere S, et al.
Randomized trial of effect of cyclical etidronate in the prevention of corticoste-
roid-induced bone loss. Ciblos Study Group. J Clin Endocrinol Metab. 1998;83:
1128-33. [PMID: 9543129]
128. Silberstein EB, Schnur W. Cyclic oral phosphate and etidronate increase
femoral and lumbar bone mineral density and reduce lumbar spine fracture rate
over three years. J Nucl Med. 1992;33:1-5. [PMID: 1730972]
129. Brumsen C, Papapoulos SE, Lips P, Geelhoed-Duijvestijn PH, Hamdy
NA, Landman JO, et al. Daily oral pamidronate in women and men with
osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year
open extension. J Bone Miner Res. 2002;17:1057-64. [PMID: 12054161]
130. Lees B, Garland SW, Walton C, Ross D, Whitehead MI, Stevenson JC.
Role of oral pamidronate in preventing bone loss in postmenopausal women.
Osteoporos Int. 1996;6:480-5. [PMID: 9116394]
131. Lufkin EG, Wahner HW, O’Fallon WM, Hodgson SF, Kotowicz MA,
Lane AW, et al. Treatment of postmenopausal osteoporosis with transdermal
estrogen. Ann Intern Med. 1992;117:1-9. [PMID: 1534476]
132. Reid IR, King AR, Alexander CJ, Ibbertson HK. Prevention of steroid-
induced osteoporosis with (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate
(APD). Lancet. 1988;1:143-6. [PMID: 2892989]
133. Ryan PJ, Blake GM, Davie M, Haddaway M, Gibson T, Fogelman I.
Intermittent oral disodium pamidronate in established osteoporosis: a 2 year
double-masked placebo-controlled study of efficacy and safety. Osteoporos Int.
2000;11:171-6. [PMID: 10793877]
Clinical Guidelines Treatment of Low Bone Density or Osteoporosis to Prevent Fractures
414 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 www.annals.org
134. Sato Y, Asoh T, Kaji M, Oizumi K. Beneficial effect of intermittent cyclical
etidronate therapy in hemiplegic patients following an acute stroke. J Bone Miner
Res. 2000;15:2487-94. [PMID: 11127214]
135. McClung MR, Wasnich RD, Recker R, Cauley JA, Chesnut CH 3rd,
Ensrud KE, et al. Oral Ibandronate Study Group. Oral daily ibandronate pre-
vents bone loss in early postmenopausal women without osteoporosis. J Bone
Miner Res. 2004;19:11-8. [PMID: 14753731]
136. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphos-
phonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753-61.
[PMID: 16702591]
137. Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM. Use of alen-
dronate and risk of incident atrial fibrillation in women. Arch Intern Med. 2008;
168:826-31. [PMID: 18443257]
138. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener
H, et al. ESPRIT team. Oestrogen therapy for prevention of reinfarction in
postmenopausal women: a randomised placebo controlled trial. Lancet. 2002;
360:2001-8. [PMID: 12504395]
139. Mosekilde L, Beck-Nielsen H, Sørensen OH, Nielsen SP, Charles P,
Vestergaard P, et al. Hormonal replacement therapy reduces forearm fracture
incidence in recent postmenopausal women—results of the Danish Osteoporosis
Prevention Study. Maturitas. 2000;36:181-93. [PMID: 11063900]
140. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al.
Randomized trial of estrogen plus progestin for secondary prevention of coronary
heart disease in postmenopausal women. Heart and Estrogen/progestin Replace-
ment Study (HERS) Research Group. JAMA. 1998;280:605-13. [PMID:
9718051]
141. Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of low-dose
continuous estrogen and progesterone therapy with calcium and vitamin D on
bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999;
130:897-904. [PMID: 10375338]
142. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrilla-
tion [Letter]. N Engl J Med. 2007;356:1895-6. [PMID: 17476024]
143. Notelovitz M, John VA, Good WR. Effectiveness of Alora estradiol matrix
transdermal delivery system in improving lumbar bone mineral density in healthy,
postmenopausal women. Menopause. 2002;9:343-53. [PMID: 12218723]
144. Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ,
Paskett ED, et al. WHI Investigators. Effects of conjugated equine estrogens on
breast cancer and mammography screening in postmenopausal women with hys-
terectomy. JAMA. 2006;295:1647-57. [PMID: 16609086]
145. Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, et al.
Multiple Outcomes of Raloxifene Evaluation Investigators. Safety and adverse
effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Ob-
stet Gynecol. 2004;104:837-44. [PMID: 15458908]
146. Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent go-
nadotropin-releasing hormone agonist-induced bone loss in men with prostate
cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841-6.
[PMID: 15292315]
147. Johnston CC Jr, Bjarnason NH, Cohen FJ, Shah A, Lindsay R, Mitlak
BH, et al. Long-term effects of raloxifene on bone mineral density, bone turn-
over, and serum lipid levels in early postmenopausal women: three-year data from
2 double-blind, randomized, placebo-controlled trials. Arch Intern Med. 2000;
160:3444-50. [PMID: 11112238]
148. Jolly EE, Bjarnason NH, Neven P, Plouffe L Jr, Johnston CC Jr, Watts SD,
et al. Prevention of osteoporosis and uterine effects in postmenopausal women taking
raloxifene for 5 years. Menopause. 2003;10:337-44. [PMID: 12851517]
149. Kung AW, Chao HT, Huang KE, Need AG, Taechakraichana N,
Loh FH, et al. Efficacy and safety of raloxifene 60 milligrams/day in
postmenopausal Asian women. J Clin Endocrinol Metab. 2003;88:3130-6.
[PMID: 12843154]
150. Meunier PJ, Vignot E, Garnero P, Confavreux E, Paris E, Liu-Leage S,
et al. Treatment of postmenopausal women with osteoporosis or low bone den-
sity with raloxifene. Raloxifene Study Group. Osteoporos Int. 1999;10:330-6.
[PMID: 10692984]
151. Michalska´ D, Stepan JJ, Basson BR, Pavo I. The effect of raloxifene after
discontinuation of long-term alendronate treatment of postmenopausal osteopo-
rosis. J Clin Endocrinol Metab. 2006;91:870-7. [PMID: 16352692]
152. Zheng S, Wu Y, Zhang Z, Yang X, Hui Y, Zhang Y, et al. Effects of
raloxifene hydrochloride on bone mineral density, bone metabolism and serum
lipids in postmenopausal women: a randomized clinical trial in Beijing. Chin
Med J (Engl). 2003;116:1127-33. [PMID: 12935394]
153. Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud C.
A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and
serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996;
11:835-42. [PMID: 8725181]
154. Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E. Addi-
tive effects of raloxifene and alendronate on bone density and biochemical mark-
ers of bone remodeling in postmenopausal women with osteoporosis. J Clin
Endocrinol Metab. 2002;87:985-92. [PMID: 11889149]
155. Rubin MR, Lee KH, McMahon DJ, Silverberg SJ. Raloxifene lowers se-
rum calcium and markers of bone turnover in postmenopausal women with
primary hyperparathyroidism. J Clin Endocrinol Metab. 2003;88:1174-8.
[PMID: 12629102]
VISIT THE
A
NNALS
BOOTH AT SUBSPECIALTY MEETINGS
Annals staff will be at these upcoming meetings:
Interscience Conference on Antimicrobial Agents and Chemotherapy/
Infectious Disease Society of America 2008, Washington, DC,
26–28 October 2008
American College of Rheumatology, San Francisco, 25–28 October 2008
American Heart Association, New Orleans, 9–11 November 2008
American Society of Hematology, San Francisco, 6–9 December 2008
Stop by the ACP/Annals booth and register to be a peer reviewer or discuss
your thoughts for submissions or topic coverage with Annals staff.
Clinical GuidelinesTreatment of Low Bone Density or Osteoporosis to Prevent Fractures
www.annals.org 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 415
Current Author Addresses: Drs. Qaseem and Snow: 190 N. Indepen-
dence Mall West, Philadelphia, PA 19106.
Dr. Shekelle: 1776 Main Street, Santa Monica, CA 90401.
Dr. Hopkins: 4301 West Markham Street, Little Rock, AR 72205.
Dr. Forciea: 3615 Chestnut Street, Philadelphia, PA 19104.
Dr. Owens: 117 Encina Commons, Stanford, CA 94305.
Annals of Internal Medicine
www.annals.org 16 September 2008 Annals of Internal Medicine Volume 149 • Number 6 W-77
