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Early Effects of Raloxifene on Clinical Vertebral Fractures at 12 Months in Postmenopausal Women With Osteoporosis
Michael Maricic, MD;
Jonathan D. Adachi, MD;
Somnath Sarkar, PhD;
Wentao Wu, MS;
Mayme Wong, PhD;
Kristine D. Harper, MD
Arch Intern Med. 2002;162:1140-1143.
ABSTRACT
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Background Raloxifene hydrochloride therapy reduces the risk for vertebral fractures
at 3 years, but the effects on clinical vertebral fractures in the first year
are not known.
Methods The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial enrolled
7705 women with osteoporosis, defined by prevalent vertebral fractures and/or
a bone mineral density (BMD) T score at or below -2.5, who were treated
with placebo or raloxifene at a dosage of 60 or 120 mg/d for 3 years. New
clinical vertebral fractures were defined as incident vertebral fractures
associated with signs and symptoms suggestive of vertebral fractures, such
as back pain, and were diagnosed by means of postbaseline adjudicated spinal
radiographs. Scheduled spinal radiographs were obtained at baseline and at
2 and 3 years. In addition, unscheduled spinal radiographs were obtained in
women who reported signs or symptoms suggestive of vertebral fracture, and
these radiographs subsequently underwent adjudication. If an adjudicated fracture
was identified, this was also considered a clinical fracture.
Results At 1 year, raloxifene, 60 mg/d, decreased the risk for new clinical
vertebral fractures by 68% (95% confidence interval [CI], 20%-87%) compared
with placebo in the overall study population, and by 66% (95% CI, 23%-89%)
in women with prevalent vertebral fractures, who are at greater risk for subsequent
fracture. The risk for clinical vertebral fractures in the raloxifene, 60
mg/d, group was decreased by 46% (95% CI, 14%-66%) at 2 years and by 41% (95%
CI, 17%-59%) at 3 years. The cumulative incidence of new clinical vertebral
fractures was lower in the group receiving raloxifene, 60 mg/d, compared with
placebo (P<.001). We found no significant differences
in the risk reductions for clinical vertebral fractures between the raloxifene
groups at 1, 2, or 3 years.
Conclusion The early risk reduction for new clinical vertebral fractures with 1
year of raloxifene treatment was similar to that reported with other antiresorptive
agents.
INTRODUCTION
ALTHOUGH VERTEBRAL fractures are estimated to occur in approximately
25% of postmenopausal women,1 less than one
third of all vertebral fractures come to clinical attention.2
Women who experience back pain due to a new vertebral fracture have functional
limitations3 and experience more days of limited
activity and bed rest.4 Vertebral fractures
are also associated with increased mortality.5
Since women who have a vertebral fracture are at greater risk for future fractures,6 any new fracture should be avoided.
Several antiresorptive therapies that are currently available for osteoporosis
prevention and treatment significantly reduced the risk for new vertebral
fractures in clinical trials lasting 3 to 5 years. Raloxifene hydrochloride,
a selective estrogen receptor modulator, reduced the risk for new vertebral
fractures in the randomized, placebo-controlled, double-blind Multiple Outcomes
of Raloxifene Evaluation (MORE) Trial in postmenopausal women with osteoporosis.7 Other antiresorptive agents, including the bisphosphonates
alendronate sodium8-9 and risedronate
sodium10-11 and salmon calcitonin
nasal spray,12 also decreased the risk for
new vertebral fractures in postmenopausal women.
Risedronate reduced the risks of new vertebral fractures, assessed in
scheduled spinal radiographs obtained at 1 year, by 61% and 65% in the multinational
and North American studies, respectively.10-11
Alendronate significantly decreased the risk for new clinical vertebral fractures
reported at 1 year by 59% in women with osteoporosis defined by prevalent
vertebral fractures, or by femoral neck BMD T scores below 2.5 SDs compared
with the mean peak BMD value in young adults.13
It is not known whether antiresorptive agents other than bisphosphonates have
similar early onset of efficacy in reducing the risk for new vertebral fractures
at 1 year. This report examines the effects of raloxifene, 60 mg/d, on the
risk for new clinical vertebral fractures at 1, 2, and 3 years.
PATIENTS AND METHODS
The MORE Trial enrolled 7705 postmenopausal women with osteoporosis,
defined by a lumbar spine or femoral neck BMD T score at or below 2.5 and/or
radiographically apparent prevalent vertebral fractures. Approximately one
third of the women in the MORE Trial had at least 1 prevalent vertebral fracture.
The inclusion and exclusion criteria are described in detail elsewhere.7 Women were randomized to treatment with raloxifene
hydrochloride at 60 or 120 mg/d or an identical-appearing placebo. All women
received daily supplements of calcium (500 mg) and cholecalciferol (400-600
IU). The 3-year skeletal efficacy results were reported previously.7
Radiologists who were masked to treatment group assignment but not temporal
sequence of the radiographs assessed vertebral fractures in the spinal radiographs
at a central laboratory, as described elsewhere.7
For the present analysis, women were grouped according to the presence or
absence of an adjudicated vertebral fracture at baseline. An adjudicated fracture
was confirmed by means of at least 2 of 3 determinations, consisting of 2
independent semiquantitative assessments and 1 quantitative morphometric measurement.
The semiquantitative assessment criteria were used to define the fracture
severity in each vertebra as 0, 1, 2, or 3, corresponding to no fracture or
a mild, moderate, or severe fracture, respectively, depending on the degree
of vertebral height loss from baseline.14 Normal
vertebrae (grade 0) had minimal deformity, with less than 20% reduction in
the anterior, middle, and posterior vertebral height. Mild vertebral deformities
(grade 1) corresponded to a 20% to 25% reduction in vertebral height. Moderate
(grade 2) and severe (grade 3) vertebral fractures had decreases in vertebral
height of 25% to 40% and more than 40%, respectively. Vertebral fractures
were also identified using quantitative morphometric criteria, consisting
of a decrease in anterior, middle, and posterior vertebral height of at least
20% and at least 4 mm. In clinical trials of osteoporosis therapies, the standard
method used to define incident vertebral fractures from radiographs consists
of a combination of semiquantitative and quantitative morphometric assessment
criteria. Incident vertebral fractures were described as new fractures in
vertebrae that were not fractured at baseline.
Clinical vertebral fractures, which result in clinically observed symptoms,
are a subgroup of all incident vertebral fractures identified using the above
assessment criteria in radiographs, since most vertebral fractures are asymptomatic.15 In this analysis, new clinical vertebral fractures
were defined as new fractures associated with signs or symptoms suggestive
of vertebral fracture, such as back pain, reported at any postbaseline visit,
and that were subsequently corroborated with radiographs and adjudicated.
Scheduled spinal radiographs were performed at 2 and 3 years. Other efficacy
end points of the MORE Trial were assessed at interim 6-month clinic visits.
Additional unscheduled radiographs were obtained at these interim visits when
patients reported symptoms of vertebral fracture, and if a new adjudicated
fracture was identified, these were also considered to be clinical fractures.
The primary analysis was the proportion of women with at least 1 new (incident)
vertebral fracture, with further analysis performed for new clinical fractures.
We analyzed the incidence of new clinical vertebral fractures by the
Pearson  2 test when the number of events in all treatment
groups was at least 10, or by Fisher exact test when the number of events
in the treatment groups ranged from 5 to 9. Statistical inference was not
performed when fewer than 5 events occurred. The cumulative incidence of new
clinical vertebral fractures observed in the placebo group and the group receiving
raloxifene, 60 mg/d, for 3 years was plotted, and statistical significance
was assessed by the log-rank test. Relative risks (RRs) and 95% confidence
intervals (CIs) were calculated using large sample procedures (Mantel-Haenszel
CI).
RESULTS
The baseline characteristics of the women in the MORE Trial cohort were
previously reported in detail by Ettinger et al,7
and are summarized briefly in Table 1.
Mean age was 66.5 years. They had been postmenopausal for a mean of 18.7 years
and had a mean body mass index (calculated as weight in kilograms divided
by the square of height in meters) of 25.2. A prevalent vertebral fracture
was present in 37.3% of the women enrolled. We found no statistically significant
differences between therapy groups in the baseline characteristics.
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Table 1. Baseline Characteristics of 7705 Postmenopausal Women With
Osteoporosis*
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Table 2 shows the number
of women in each group who had at least 1 new clinical vertebral fracture
during years 1, 2, and 3 in the study. In the first year, 19 women in the
placebo group and 6 women in the group receiving raloxifene, 60 mg/d, had
at least 1 new clinical vertebral fracture, resulting in a statistically significant
68% reduction in the RR of a new clinical vertebral fracture (Figure 1). Among women who had a prevalent vertebral fracture, the
60-mg/d dosage of raloxifene significantly decreased the RR for a new clinical
vertebral fracture by 66% at 1 year (Figure
1). Among women with no prevalent vertebral fracture, 2 women (0.1%)
in the placebo group and none in the 60-mg/d raloxifene group had a new clinical
fracture at 1 year.
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Table 2. Incidence of New Clinical Vertebral Fractures in Postmenopausal
Women With Osteoporosis Treated With Placebo or Raloxifene for 3 Years*
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Figure 1. Raloxifene hydrochloride, 60 mg/d,
decreased the risk for new clinical vertebral fractures in the Multiple Outcomes
of Raloxifene Evaluation (MORE) Trial. A, Decreased fracture risk in the total
study population, consisting of women with and without prevalent vertebral
fractures. Among women who had a baseline radiograph, 37.4% had prevalent
vertebral fractures. RR indicates relative risk; CI, confidence interval.
B, Raloxifene, 60 mg/d, also decreased the risk for new clinical vertebral
fractures in those women with prevalent fractures, who are at greater risk
for subsequent fractures.
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The cumulative incidence of new clinical vertebral fractures in the
60-mg/d raloxifene group was lower (P<.001) than
in the placebo group (Figure 2).
Like the significant risk reduction observed in the first year (P<.001), the cumulative RRs for new clinical vertebral fractures
were 0.54 (95% CI, 0.34-0.86) at year 2, and 0.59 (95% CI, 0.41-0.83) at year
3.
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Figure 2. The cumulative incidence of new
clinical vertebral fractures in the groups receiving placebo and raloxifene
hydrochloride, 60 mg/d. The difference between the groups was statistically
significant, as determined by means of the log-rank test (P<.001).
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For the group receiving raloxifene 120 mg/d, the RRs were 0.21 (95%
CI, 0.07-0.62) at year 1, 0.35 (95% CI, 0.20-0.59) at year 2, and 0.48 (95%
CI, 0.33-0.70) at year 3. The decreased risks for clinical vertebral fractures
were not significantly different between the 2 raloxifene groups at 1, 2,
or 3 years.
COMMENT
Raloxifene at a dosage of 60 mg/d reduced the risk for new clinical
vertebral fractures by 68% in the first year in postmenopausal women with
osteoporosis, and by 66% in women with prevalent vertebral fractures. The
cumulative incidence of new clinical vertebral fractures was significantly
lower in this group, compared with the placebo group. Significant RR reductions
for new clinical vertebral fractures were also observed at 2 and 3 years.
The decreased RRs were similar for the raloxifene dosages of 60 and 120 mg/d.
The risk reductions for new clinical vertebral fractures were also observed
at 3 years with alendronate and risedronate. Only the risedronate trials included
scheduled spinal radiographs for all women at 1 year, irrespective of clinical
symptoms, and the observed risk reductions would be a closer estimate of the
true efficacy of the drug for vertebral fracture.
Because of the small number of events, our study had inadequate statistical
power to determine whether the risk reduction for clinical vertebral fractures
was different for each individual year of the study. Data from the MORE Trial
suggest that symptomatic vertebral fractures are usually associated with moderate
or severe vertebral compression, and in the MORE Trial, significant reductions
in moderate and severe vertebral compression fractures are observed through
3 and 4 years (Ethel Siris, MD, JDA, Ying Lu, PhD, Thomas Fuerst, PhD, Gerald
Crans, PhD, MW, KDH, Harry Genant, MD, unpublished data, November 1999). The
primary limitation to the use of self-report of clinically apparent vertebral
fractures is that approximately two thirds of vertebral fractures do not produce
clinical symptoms and would not be reported.2
Therefore, the 68% risk reduction for new clinical vertebral fractures may
underestimate the actual 1-year efficacy of raloxifene for vertebral fractures.
Unlike the risedronate study, the MORE Trial did not prospectively assess
vertebral fractures by means of scheduled spinal radiographs at 1 year.
Antiresorptive agents primarily act by inhibiting bone resorption to
transiently decrease the bone remodeling space.16
Whether these early transient changes may accumulate to sufficiently support
bone strength is unknown, but the early onset of the effect and the significant
reductions in the risk for new vertebral fractures with raloxifene, alendronate,
and risedronate suggest that this may be possible.
Women with prevalent vertebral fractures experienced a significantly
decreased incidence of new clinical vertebral fractures after 1 year of raloxifene
therapy. We found insufficient numbers of clinical vertebral fracture events
in women without prevalent vertebral fractures at this time to draw similar
conclusions. The present study demonstrates that the skeletal effect of raloxifene
occurs with a rapid onset at 1 year, similar to that observed with other antiresorptive
agents.
AUTHOR INFORMATION
Accepted for publication September 27, 2001.
Eli Lilly and Company, Indianapolis, Ind, provided funding for this
study.
This study was presented in part as a poster at the 64th Annual Meeting
of the American College of Rheumatology, Philadelphia, Pa, October 31, 2000.
We thank Michele Hill for editorial assistance.
Corresponding author: Michael Maricic, MD, Section of Rheumatology,
Southern Arizona Veterans Affairs Health Care System, 3601 S Sixth Ave, Tucson,
AZ 85723 (e-mail: mikemaricic{at}msn.com).
Reprints: Mayme
Wong, PhD, Lilly Corporate Center, Drop Code 2244, Eli Lilly and Company,
Indianapolis, IN 46285 (e-mail: wong_mayme{at}Lilly.com).
From the Section on Rheumatology, Department of Medicine, Southern
Arizona Veterans Affairs Health Care System, Tucson (Dr Maricic); Department
of Rheumatology, St Joseph's Hospital, McMaster University, Hamilton, Ontario
(Dr Adachi); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis,
Ind (Drs Sarkar, Wong, and Harper and Mr Wu). Dr Maricic has received research
funding for conducting clinical trials, has received honoraria for serving
as a speaker, has served as a paid consultant, and is on the scientific advisory
board for Eli Lilly and Company.
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