Context.— Alendronate sodium reduces fracture risk in
postmenopausal women who have vertebral fractures, but its effects on
fracture risk have not been studied for women without vertebral
fractures.
Objective.— To test the hypothesis that 4 years of
alendronate would decrease the risk of clinical and vertebral fractures
in women who have low bone mineral density (BMD) but no vertebral
fractures.
Design.— Randomized, blinded, placebo-controlled trial.
Setting.— Eleven community-based clinical research centers.
Subjects.— Women aged 54 to 81 years with a femoral neck BMD
of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no
vertebral fracture; 4432 were randomized to alendronate or placebo and
4272 (96%) completed outcome measurements at the final visit (an
average of 4.2 years later).
Intervention.— All participants reporting calcium intakes of
1000 mg/d or less received a supplement containing 500 mg of calcium
and 250 IU of cholecalciferol. Subjects were randomly assigned to
either placebo or 5 mg/d of alendronate sodium for 2 years followed by
10 mg/d for the remainder of the trial.
Main Outcome Measures.— Clinical fractures confirmed
by x-ray reports, new vertebral deformities detected by morphometric
measurements on radiographs, and BMD measured by dual x-ray
absorptiometry.
Results.— Alendronate increased BMD at all sites studied
(P<.001) and reduced clinical fractures from 312 in the
placebo group to 272 in the intervention group, but not significantly
so (14% reduction; relative hazard [RH], 0.86; 95% confidence
interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by
36% in women with baseline osteoporosis at the femoral neck (>2.5
SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82;
treatment-control difference, 6.5%; number needed to treat [NNT],
15), but there was no significant reduction among those with higher BMD
(RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of
radiographic vertebral fractures by 44% overall (relative risk, 0.56;
95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60).
Alendronate did not increase the risk of gastrointestinal or other
adverse effects.
Conclusions.— In women with low BMD but without vertebral
fractures, 4 years of alendronate safely increased BMD and decreased
the risk of first vertebral deformity. Alendronate significantly
reduced the risk of clinical fractures among women with osteoporosis
but not among women with higher BMD.
OSTEOPOROSIS results in millions of
fractures,1 more than 400,000 hospital admissions,
more than 44 million patient-days in nursing homes, and $13.8 billion
in health care expenditures among women and men yearly in the United
States alone.2 Alendronate sodium increases the density of
mineral in bone and reduces the risk of vertebral
fractures in women with osteoporosis.3,4 In the Fracture
Intervention Trial (FIT), we showed that 3 years of alendronate also
reduced the risk of hip and wrist fractures by about 50% among women
who had low bone mineral density (BMD) and vertebral
fractures.5 However, only 10%
to 15% of postmenopausal women have vertebral
fractures,6,7 and the effectiveness of treatments for the
larger group of women who have low BMD but no prior vertebral fractures
has not been specifically studied. The clinical fracture arm of FIT was
designed to test the hypothesis that 4 years of treatment with
alendronate would also reduce the risk of clinical fractures in
postmenopausal women who have low BMD but no vertebral fracture. As
planned, we analyzed the effect of alendronate in subgroups of women by
tertile of initial levels of femoral neck BMD.
The trial was conducted at 11 clinical centers in the United States,
with a coordinating center at the University of California, San
Francisco.8 The FIT had 2 arms: the vertebral fracture
arm,5 which included women who had vertebral fractures, and
the clinical fracture arm, which included women without vertebral
fractures and is the subject of this article.
Selection of Participants
We aimed to enroll 4000 women aged 55 through 80 years who had been
postmenopausal for at least 2 years and had femoral neck BMD of 0.68
g/cm2 (QDR-2000, Hologic Inc, Waltham, Mass) or less. At
the time of enrollment, this was believed to correspond to a BMD value
of at least 2 SDs below the mean of normal young adult white women,
based on the manufacturer's reference values. Subsequently, results
from the Third National Health and Nutritional Examination Survey
indicated that our inclusion criteria instead corresponded to 1.6 SD or
more below the normal young adult mean.6 Consequently,
about one third of women in the trial actually had higher BMD than
expected. Women were recruited principally by mass mailings (Figure
1).
We excluded women who had recent peptic ulcers or ulcers that required
hospitalization, dyspepsia requiring daily treatment, significant renal
or hepatic dysfunction, medical problems that precluded 3 years of
participation, severe malabsorption, blood pressure exceeding 210 mm Hg
systolic or 105 mm Hg diastolic, myocardial infarction within 6 months,
unstable angina, hypothyroidism, hyperthyroidism, or
hyperparathyroidism. We also excluded women who had taken estrogen or
calcitonin within the preceding 6 months or bisphosphonates or sodium
fluoride (>1 mg/d) at any time. Although women taking estrogen were
excluded from entry into the trial, 246 (11.1%) in the placebo group
and 204 (9.2%) in the alendronate group took estrogen at some time
during the study. All women provided written informed consent and the
protocol was approved by the appropriate institutional review boards.
Women were randomized in blocks of 10 that were stratified within
clinical center. Treatment was assigned by computer-generated codes.
Each bottle of medication was labeled with a nonrepeating allocation
number that could be revealed only for safety concerns. Those who
generated the allocation schedule were not allowed to communicate with
anyone who assigned the study drugs.
The dosage of alendronate sodium was 5 mg/d for 2 years but was
increased to 10 mg/d at the second annual visit because other trials
suggested that 10 mg/d had greater effects on BMD. Participants were
instructed to take the study drug with at least 120 mL (4 oz) of water
in a fasting state and not lie down or eat or drink any other food or
liquid for at least a half hour. Prescription medications that had to
be taken in the fasting state could be taken before breakfast.
Participants were instructed to take calcium supplements, antacids,
tetracycline, sucralfate, or bile acid–binding resins after breakfast.
Eighty-two percent of participants in each treatment group had dietary
calcium intakes of less than 1000 mg/d; they were asked to take a
daily supplement containing 500 mg of elemental
calcium (OsCal) and 250 IU of cholecalciferol (vitamin D). Women had
study visits semiannually and all information regarding clinical
fractures was forwarded to the coordinating center.
Clinical Fractures.— A clinical fracture was defined as one diagnosed by a physician. Self-reports of fractures were
confirmed by written reports of radiographs or other tests. We excluded
pathologic fractures or fractures due to trauma sufficient to fracture
a normal bone in most young adults. Facial and skull fractures were
excluded because they are not associated with low BMD.9
Before study unblinding, subgroups of clinical fractures were defined
as nonspine fractures, hip fractures, wrist fractures, clinical
vertebral fractures and clinical fractures other than a wrist, spine,
or hip fracture. Participants could have more than 1 type of fracture
and so could appear in more than 1 category.
Radiographic Evidence of Vertebral Fractures.— Lateral spine radiographs were obtained according to
published guidelines10 at baseline and 4 years after
randomization. Women with vertebral fractures assessed by
morphometry5,10-12 were excluded from this arm of the
study.
A new deformity, or radiographic vertebral fracture, was defined as a
decrease of 20% and 4 mm or more in any vertebral height from baseline
to the end of the study5,12 and confirmed by a repeat
measurement of the involved vertebral body. All assessments were
blinded to treatment allocation.
Bone Mineral Density.— Bone mineral density was
measured at the hip, posterior-anterior spine, and in the whole body on
all participants using Hologic QDR 2000 densitometers. Forearm BMD was
measured (one third of the way up from the wrist to the elbow) in a
20% random sample of participants and lateral spine BMD was measured
on 82% of participants. All BMD measurements were repeated annually
except total body BMD, which was obtained at the start and end of the
study. Quality control measures have been detailed
elsewhere.8
Stature.— Height was calculated as the mean of 2 repeat measurements using Harpenden stadiometers (Holtain Ltd,
Crymmych, Pembrookshire, England).
Adverse Experiences.— Patients were questioned at each contact regarding adverse events, defined as any untoward condition,
including minor illnesses such as common colds. We analyzed all adverse
experiences, including those requiring hospitalization or
discontinuation of study medication. Because of reports about
bisphosphonates and upper gastrointestinal tract
disorders,13 we analyzed upper gastrointestinal tract
events by specific symptoms and diagnoses.
We maintained blinding in several ways. Collection and review of data
were blinded to treatment assignment. Results of bone densitometry
during follow-up were not available to participants or clinicians
except when bone loss (monitored by the coordinating center) exceeded
predetermined rates (8% over 1 year, 10% over 2 years, 12% over 3
years, etc, at the total hip or posterior-anterior spine). The
appropriate clinical center investigator was informed of the bone loss
but not the treatment assignment, and he/she, in turn, informed the
participants or their primary care physicians. Finally, treatment
assignments were kept in a locked file by 1 statistician at the
coordinating center who was responsible for preparing reports to the
data safety and monitoring board.
Assuming a 4% annual incidence of clinical fracture in placebo-treated
women, the trial required 4000 women to detect a 25% decrease in risk
with 90% power and an α level of .05.8 We recruited 4432
women and observed a 3.5% annual incidence of fracture in the placebo
group, which provided 88% power to detect a 25% reduction in risk.
Clinical fractures and adverse experiences are reported as
the proportion of
women with 1 or more events. We used survival
analysis with the log-rank test to analyze and test the statistical
significance of differences between treatment groups. We present the
results as the number and percentage of women with fractures along with
relative hazards (RHs) and 95% confidence intervals (CIs) calculated
by the likelihood ratio method.14
We analyzed the proportion of women with 1 or more radiographically
detected vertebral fracture and present the rates in each group along
with the relative risk (RR), calculated as the ratio of the proportion
of women with fractures in the alendronate group compared with the
placebo group. We used the Mantel-Haenszel χ2
statistic to test the significance of differences between treatment
groups. We used t tests to compute the statistical
significance of differences between the treatment groups for changes in
BMD and height. All P values are 2-sided. We also estimated
the number needed to treat (NNT) for 4.25 years to prevent 1 fracture.
All analyses followed an intention-to-treat design.
Before unblinding, we planned to analyze the effects of
alendronate on the risk of clinical fractures, vertebral fractures, and
bone densities in subgroups stratified by tertile of baseline BMD; in
this analysis we use femoral neck BMD. The cutoff for the bottom
tertile (femoral neck BMD <0.571 g/cm2) represented a T
score of −2.55 or less, which is similar to the World Health
Organization definition of osteoporosis as a T score of less than
−2.5.12 The middle tertile was 2.06 (0.631
g/cm2) to 2.56 SD, and the highest tertile was 1.6 (0.681
g/cm2) to 2.05 SDs below the normal young adult mean. Thus,
for simplicity of presentation, we report the results in 3 ranges of T
scores: −2.5 or less, −2.0 to −2.5, and −1.6 to −2.0 or more.
We tested the statistical significance of any interactions between BMD
and the effect of treatment on the risk of clinical fractures by
performing a proportional hazards analysis, which included terms for
treatment, BMD (continuous), and treatment-by-BMD interaction.
An independent data and safety monitoring board examined end
points and adverse events by treatment group semiannually. Adjustments
for repeated tests of significance required P = .046 for
statistical significance of the main result.
A total of 4432 women were randomized, 2214 to alendronate
and 2218 to placebo (Figure 1). Participants had a mean age of 68
years, 97% were white, and potential confounding variables were
equally distributed between the 2 treatment groups (Table
1). Subjects were followed up for an average of
4.2 years; closeout contacts were completed by 4272 (96%) of the
participants. At closeout, 82.5% of surviving participants randomized
to placebo and 81.3% of those assigned to alendronate were still
taking study medication. Of those taking study medication, 96% in each
of the 2 treatment groups had taken at least 75% of their pills.
Thirty-four participants (22 in the placebo group and 12 in the
alendronate group) had stopped taking their study medication because
their rate of bone loss exceeded predetermined limits.
Compared with placebo, treatment with alendronate
increased average BMD at all measured sites (Figure
2). After 4 years, women in the placebo group lost
an average of 0.8% of femoral neck BMD, while women in the alendronate
group gained 3.8% (difference, 4.6%; P<.001). The placebo
group lost an average of 1.6% of BMD in the total hip, while the
alendronate group gained 3.4% (difference, 5.0%; P<.001).
In the lumbar spine, the placebo group gained 1.5% vs an 8.3% gain in
the alendronate group (difference, 6.6%; P<.001). Women who
received alendronate also gained significantly more BMD than the
placebo group in the trochanter (difference, 6.8%), total body
(difference, 2.0%), lateral spine (difference, 7.1%), and ultradistal
forearm (difference, 3.1%).
Alendronate increased BMD similarly in all subgroups of initial BMD.
For example, it increased femoral neck BMD by 4.6% (95% CI,
4.0%-5.1%) in those with baseline femoral neck T scores of −2.5 or
less, 4.8% (95% CI, 4.2%-5.3%) in those with T scores of −2.0 to
−2.5, and 4.8% (95% CI, 4.2%-5.4%) in those with T scores of −1.6
to −2.0 or more.
Clinical fractures, the primary end point, occurred in 312 women
(14.1%) in the placebo and 272 women (12.3%) in the alendronate group
(RH, 0.86; 95% CI, 0.73-1.01) (Table 2 and Figure
3). Twenty-four women (1.1%) in the placebo group
and 19 women (0.9%) in the alendronate group had hip fractures (14%
reduction; RH, 0.79; 95% CI, 0.43-1.44), while 70 (3.2%) in the
placebo group and 83 (3.7%) in the alendronate group fractured a wrist
(RH, 1.19; 95% CI, 0.87-1.64). Fewer women assigned to alendronate (n
= 182, 8.2%) than to placebo (n = 227, 10.2%) had fractures at sites
other than spine, hip, or wrist (RH, 0.79; 95% CI, 0.65-0.96;
placebo-treatment difference, 2.0%; NNT, 50).
The effect of treatment on the risk of clinical fractures
depended on initial femoral neck BMD (P = .01 for the
interaction) (Table 3 and Figure
4). Alendronate significantly reduced the risk of
clinical fractures by 36% (RH, 0.64; 95% CI, 0.50-0.82;
placebo-treatment difference, 6.5%; NNT, 15) in women whose initial
femoral neck T score was −2.5 or less. However, 4 years of
alendronate did not significantly affect risk of clinical fracture in
those with higher BMD. We observed a 22% lower risk of clinical
fracture in those whose T scores were more than 2.0 SDs below the
normal mean (RH, 0.78; 95% CI, 0.65-0.94; placebo-treatment
difference, 3.3%; NNT, 30) (Figure 4). Alendronate did not decrease
the risk of fracture among
subjects whose initial T scores were greater than
−2.5 (RH, 1.08; 95% CI, 0.87-1.35).
In post hoc analyses, alendronate reduced the risk of hip
fractures by 56% among women with a femoral neck T score of −2.5 or
less: 18 (2.2%) in the placebo group vs 8 (1.0%) in the alendronate
group (RH, 0.44; 95% CI, 0.18-0.97; placebo-treatment difference,
1.2%; NNT, 81). There was no reduction in risk among those whose
femoral neck T scores were more than −2.5: 6 (0.4%) in the placebo
group vs 11 (0.8%) in the alendronate group (RH, 1.84; 95% CI,
0.70-5.36).
The effect of alendronate on the risk of wrist fractures
also varied by baseline femoral neck BMD. There was no significant
reduction among women with a T score of −2.5 or less: 38 (4.7%) in
the placebo and 34 (4.2%) in the alendronate group (RH, 0.88; 95% CI,
0.55-1.40). Similarly, we observed no reduction in risk among women
with T scores of −2.0 to −2.5: 20 (2.8%) in the placebo group vs 27
(3.7%) in the alendronate group (RH, 1.33; 95% CI, 0.75-2.4). Among
those whose femoral neck T scores were more than −2.0, more fractures
occurred in the treatment group (n = 22, 3.3%) than in the placebo
group (n = 12, 1.7%; RH, 1.9; 95% CI, 1.0-4.0;
placebo-treatment difference, 1.6%).
Stratification of the results by BMD of the total hip, spine, or
other sites indicated that alendronate consistently decreased the risk
of nonspine fractures among women with BMD T scores of −2.5 or less
but not among women with BMD T scores of more than −2.0. The apparent
threshold for a significant effect of treatment on risk of clinical
fractures varied by BMD measurement site from a T score of −2.5 or
less at the femoral neck and spine to less than −2.0 at the total hip.
Radiographic Vertebral Fractures
We obtained final follow-up radiographs for 4134
participants (95% of those surviving at that time). Alendronate
reduced the overall risk of new radiographic vertebral fractures by
44%: 78 women (3.8%) in the placebo group developed at least 1 new
fracture compared with 43 (2.1%) in the alendronate group (44%
reduction; RR, 0.56; 95% CI, 0.39-0.80; P = .001;
placebo-treatment difference, 1.7%; NNT, 60) (Table 2). The risk of
radiographic vertebral fractures was highest among women with the
lowest BMD. Consequently, estimated NNTs increased from 35 among women
with a femoral neck BMD T score of less than −2.5 to 59 for those with
T scores of −2.5 to −2.0, and to approximately 363 for those with T
scores of −2.0 to −1.6.
Alendronate also reduced the mean loss of height by 1.5 mm over 4
years: 8.5 mm in the placebo group vs 7.0 mm in the alendronate group
(P<.001).
Permanent discontinuations of study medication due to adverse
experiences were similar in the 2 groups (Table
4). Similarly, there were no significant
differences in rates of death or adverse experiences resulting in
hospitalization. There were no significant differences between the
groups in rates of abdominal pain, esophagitis, esophageal ulcer,
gastric ulcer, duodenal ulcer, or other adverse upper gastrointestinal
tract effects.
We previously showed that alendronate decreased the risk
of vertebral, hip, and wrist fractures by about 50% and all clinical
fractures by 28% among women with vertebral fractures.5 We
have now found that 4 years of alendronate also decreased the risk of
all clinical fractures, hip fractures, and vertebral deformity in women
with hip BMD T scores below −2.5 who did not have a vertebral
fracture. An analysis by the National Osteoporosis Foundation concluded
that estrogen or alendronate should be offered to postmenopausal women
who have either vertebral fractures or osteoporosis confirmed by bone
densitometry.15 Our findings support those recommendations
for the use of alendronate.
Although alendronate increased BMD to a similar degree
regardless of initial density, we did not observe a significant
decrease in the risk of clinical fractures in nonosteoporotic women. It
is important to note that our study was not designed to pinpoint a
threshold for this effect; it varied between T scores of −2.5 or less
at the femoral neck and spine to −2.0 or less at the
total hip measurement sites. Why alendronate
reduced clinical fractures more effectively in those with the lowest
BMD is not clear. Alendronate may increase bone strength at least in
part by decreasing the number of resorption pits on bone
surfaces16-18; this might make a critical difference for
the most fragile bones.
Alendronate reduced the risk of radiographically detected
vertebral fractures by about half. Although most vertebral deformities
elude clinical diagnosis, many cause pain and
disability.19,20 Women with radiographic vertebral
fractures have an increased risk of vertebral, hip, or other
fractures.21,22 Thus, prevention of the first radiographic
evidence of vertebral fracture may prevent disability and herald a
decreased risk of other types of fractures. One needs to treat
relatively few patients with osteoporosis, who have a high risk of
fractures, to prevent a radiographic vertebral fracture, clinical
fracture, or hip fracture. Although NNT estimates are not precise, it
may be necessary to treat a few hundred women to prevent 1 radiographic
vertebral fracture among women with a femoral neck T score of −2.0 or
more.
In 2 previous studies, alendronate reduced the risk of wrist fractures
by 50% in women with vertebral fractures or
osteoporosis.4,5 In contrast, we found no overall reduction
in risk of wrist fracture; alendronate appeared to increase the risk of
wrist fractures in women with a femoral neck T score of more than
−2.0.
It is not clear how long alendronate should be continued.
To our knowledge, there are no data and no prospective study is under
way to estimate the effect of more than 4 years of alendronate on risk
of fractures. Treatment beyond 4 years may continue to improve or
preserve BMD and maintain reduced bone turnover; this is being studied.
Much of the antifracture effect of alendronate may be caused by
reduction in bone resorption that occurs early and is sustained but
does not increase over time.16,23-25 Turnover repairs
naturally accumulating microscopic damage.26 There is no
evidence that alendronate has detrimental effects on bone strength,
microscopic bone structure, or fracture healing27; the
effects of more than 4 years of treatment deserve study. Additionally,
alendronate accumulates in bone and recirculates when bone containing
alendronate is remodeled.27 Thus, many years of treatment
may produce self-sustaining concentrations of alendronate in bone such
that the skeletal benefits of alendronate may continue after treatment
is stopped.28 On the other hand, if alendronate were to
cause an adverse effect that has not yet been recognized, endogenous
exposure to alendronate would also continue after stopping treatment.
Our results indicate that it would take more than 4 years of treatment
to produce a substantial reduction in risk of clinical fractures in
women who do not have osteoporosis. Some physicians may recommend
long-term treatment with alendronate to preserve the density and
structural integrity of bone in women without osteoporosis. Others may
decide that it would be more prudent and cost-effective to limit
alendronate treatment to women with osteoporosis, for whom there is
clear evidence of reduction in risk of clinical fractures.
Four years of alendronate therapy did not significantly increase the
risk of abdominal symptoms or gastrointestinal diagnoses. The risk of
esophagitis, which has been occasionally reported with alendronate
therapy,13 was very low and not significantly different
from placebo. We carefully instructed our participants to take their
medication with at least 120 mL (4 oz) of water and not to lie down for
a half hour. With the exception of some cases of esophagitis, our
results indicate that when patients take alendronate correctly,
upper gastrointestinal tract problems should not be attributed to
alendronate and usually do not necessitate stopping treatment.
We conclude that 4 years of treatment with alendronate safely increases
bone density and decreases the risk of radiographic vertebral fractures
among women with low BMD. Alendronate treatment reduces the risk of
clinical fractures among women with osteoporosis but not among those
with hip or spine T scores of −2.0 or more. The antifracture
effectiveness of more than 4 years of treatment, especially among women
without osteoporosis, is unknown.
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