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small fraction, which is unevenly distributed
between cancellous and cortical bone, seems
unlikely to change bone mechanical properties.
Since 1999, oral risedronate has also been
available on the market for the treatment of
postmenopausal osteoporosis. Risedronate has
shown benefits for BMD and risk of fracture in
the Vertebral Efficacy with Risedronate Therapy
(VERT) trial and in the Hip Intervention Pro-
gram (HIP) trial
15–17
. Both alendronate and rise-
dronate are now available in once-weekly formu-
lations approved on the basis of studies showing
BMD gains comparable to those seen with daily
formulations of both drugs
18,19
.
The appropriate way to evaluate the relative
efficacy of two drugs is to examine evidence from
a head-to-head clinical comparison.
The FACT (Fosamax™ Actonel
®
Comparison
Trial) was a randomized, double-blind, active-
comparator study that evaluated 1053 post-
menopausal women at 77 US sites. The patient
population consisted of community-dwelling,
ambulatory women who were at least 40 years of
age (or at least 25 years of age if surgically
menopausal) and postmenopausal for at least 6
months. Patients were required to have osteo-
porosis, defined as a BMD T-score of at least
–2.0 at the hip trochanter, total hip, femoral
neck or lumbar spine. Patients were excluded if
they were taking or had recently taken any treat-
ments that might influence bone turnover. As
recommended by the prescribing information for
alendronate, patients with abnormalities of the
esophagus that delay emptying (i.e. stricture,
achalasia) were excluded; there were no other
gastrointestinal (GI) exclusions
20
.
The mean age of patients was 64.5 years, and
the mean time since menopause was 18.5 years.
Approximately 95% of patients in each group
were Caucasian, and a mean of 25% in each
group had a history of an upper-GI disorder.
Almost half of all randomized patients had a his-
tory of hip, spine or wrist fracture, and almost
one-third had experienced a fracture after the age
of 45.
Patients were randomized 1: 1 to receive 12
months of therapy with either alendronate 70 mg
once weekly plus a risedronate placebo once
weekly, or risedronate 35 mg once weekly plus an
alendronate placebo once weekly. Patients were
instructed to take a minimum of 1000 mg of cal-
cium and 400 IU of vitamin D daily.
The primary objective of this study was to
evaluate the mean percentage change from base-
line in hip trochanter BMD after 12 months of
treatment. Secondary objectives included the dif-
ference between treatment groups in mean per-
centage change from baseline in total hip,
femoral neck and lumbar spine BMD at 12
months, and the mean percentage change from
baseline in biochemical markers of bone turnover
(serum bone-specific alkaline phosphatase
(BSAP), N-terminal propeptide of type I procol-
lagen (PINP), serum C-telopeptide (CTx) and
urinary NTx) at 3, 6 and 12 months. Other sec-
ondary objectives were the difference between
treatment groups in the percentage of patients
with BMD gains of at least 0% and 3%, the
mean percentage change in BMD at all sites at 6
months, and overall safety and tolerability,
including percentage of patients with any upper-
GI adverse events at 12 months.
Table 4 shows mean BMD values at baseline
in both treatment groups at the hip and the
spine: baseline T-scores were similar in the two
groups.
At baseline, mean BMD values at the hip
trochanter were 0.571 and 0.572 g/cm
2
in the
alendronate and risedronate groups, respectively.
The mean percentage change from baseline was
3.4% with alendronate and 2.1% with rise-
dronate, representing a treatment difference of
1.4% in favor of alendronate (95% confidence
interval (CI) 0.8–1.9%, p < 0.001) (Figure 4).
Table 4 Mean bone mineral density values (T-
scores) at baseline
Alendronate Risedronate Total
Site (n = 520) (n= 533) (n = 1053)
Trochanter –1.58 –1.58 –1.58
Total hip –1.76 –1.78 –1.77
Femoral neck –2.12 –2.16 –2.14
Lumbar spine –2.26 –2.23 –2.24
POSTMENOPAUSAL OSTEOPOROSIS
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The effect of alendronate became evident by
month 6 (p < 0.001 vs. risedronate).
The mean baseline total hip BMD was 0.750
(alendronate) and 0.749 g/cm
2
(risedronate),
respectively. At month 12, the mean total hip
BMD increased by 2.2% from baseline in the
alendronate group and by 1.2% in the rise-
dronate group. The treatment difference was
1.1% (95% CI 0.7–1.4%, p < 0.001 vs. rise-
dronate) (Figure 5).
At baseline, the mean BMD at the femoral
neck was 0.660 and 0.654 g/cm
2
in the alen-
dronate and risedronate groups, respectively. The
mean percentage change from baseline was 1.6%
with alendronate and 0.9% with risedronate.
The treatment difference at 12 months was 0.7%
(95% CI 0.2–1.29%, p = 0.005 vs. risedronate)
(Figure 6).
The mean baseline posteroanterior (PA)
lumbar spine BMD was 0.839 (alendronate)
and 0.837 g/cm
2
(risedronate), respectively.
Lumbar spine BMD increases were 3.7% for
alendronate and 2.6% for risedronate. This
finding reflected a treatment difference of
1.2% (95% CI 0.7–1.6%, p < 0.001 vs. rise-
dronate) (Figure 7).
The proportion of patients who experienced a
PA lumbar spine BMD decrease of at least 3%
Baseline
Mean % change
Month 6 Month 12
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Alendronate (n = 464)
Risedronate (n = 481)
2.1%
3.4%
p < 0.001
p < 0.001
Figure 4 Mean percentage change from baseline of bone mineral density at the hip trochanter
Baseline
Mean % change
Month 6 Month 12
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Alendronate (n
= 464)
Risedronate (n = 481)
1.2%
2.2%
p < 0.001
p < 0.001
Figure 5 Mean percentage change from baseline of bone mineral density at the total hip
USE OF ALENDRONATE IN OSTEOPOROSIS TREATMENT
295
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was significantly higher in the risedronate group
(4%) than in the alendronate group (1%)
(p = 0.008). Conversely, the proportion of
patients who experienced BMD gains of at least
0%, 3% and 5% was significantly higher in the
alendronate group (all p < 0.001 vs. risedronate).
Hip trochanter data were similar to those at
the PA lumbar spine: the proportion of patients
who experienced a BMD decrease at the hip
trochanter of at least 3% was significantly higher
with risedronate (11%) than with alendronate
(5%) (p < 0.001). Conversely, a significantly
higher proportion of patients in the alendronate
group experienced BMD gains of at least 0%
(p < 0.001), 3% (p =0.002) and 5% (p < 0.001).
At all time points (months 3, 6 and 12), alen-
dronate produced significantly (p < 0.001)
greater decreases in markers of bone resorption
(NTx and CTx) than did risedronate. Differences
in favor of alendronate became evident from as
early as month 3 (Figure 8). NTx reductions of
53% (alendronate) and 40% (risedronate) were
observed at month 12. This represented a treat-
ment difference of 13% (95% CI –16.6 to –8.5,
p < 0.001 vs. risedronate)
10
.
At month 12, mean CTx reductions of 74%
and 55% were observed with alendronate and
risedronate, respectively, representing a treat-
ment difference of 19% (95% CI –22.7 to –15.6,
p < 0.001 vs. risedronate).
296
Baseline
Mean % change
Month 6 Month 12
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Alendronate (n
= 464)
Risedronate (n = 481)
0.9%
1.6%
p = 0.005
p = 0.035
Figure 6 Mean percentage change from baseline of bone mineral density at the femoral neck
Baseline
Mean % change
Month 6 Month 12
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Alendronate (n
= 466)
Risedronate (n = 483)
2.6%
3.7%
p < 0.001
p = 0.002
Figure 7 Mean percentage change from baseline of bone mineral density at the posteroanterior lumbar spine
POSTMENOPAUSAL OSTEOPOROSIS
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In addition to reducing markers of bone
resorption, alendronate produced significantly
(p < 0.001) greater decreases in markers of bone
formation (BSAP and PINP) than risedronate at
all time points (months 3, 6 and 12). Together,
these results indicated an overall reduction in
bone turnover from as early as month 3 (Figure
9). BSAP value decreases of 41% and 28% were
observed at month 12 in the alendronate and
risedronate groups, respectively. This repre-
sented a treatment difference of 13% (95% CI
–15.3 to –9.6, p < 0.001 vs. risedronate). At
month 12, PINP mean values decreased by 64%
and 48% with alendronate and risedronate,
respectively, representing a treatment difference
of 16% (95% CI –18.9 to –12.9, p < 0.001 vs.
risedronate).
Overall, a clinical adverse experience was
reported by 76% of patients in each treatment
group. However, only fewer than a third of these
were drug-related; the rate of drug-related
adverse experiences was 23% with alendronate
and 21% with risedronate. Serious adverse expe-
riences were uncommon, with rates of 9% in the
alendronate group and 8% in the risedronate
group. Thirty-three patients in each group dis-
continued due to an adverse experience.
There were no significant differences between
treatment groups in the clinical adverse-experi-
ence profile. Upper-GI adverse experiences were
reported by 22.5% of patients in the alendronate
group and 20.1% of patients in the risedronate
group. These events resulted in discontinuation
in a minority of patients: 2.5% in the alen-
dronate group and 3% in the risedronate group.
There were no significant differences between
treatment groups in the upper-GI adverse-
experience profile.
Superiority of weekly alendronate versus
weekly risedronate at marketed doses in reducing
bone turnover and increasing BMD represents an
essential finding for distinguishing the efficacies
of the two drugs. Bone turnover is the major
driver of fracture risk: it characterizes the rela-
tionship between bone resorption and bone for-
mation. When bone resorption exceeds bone for-
mation, bone is lost. The primary mechanism of
action of bisphosphonates is inhibition of bone
resorption, resulting in reduced bone turnover.
The reduced rate of bone turnover leads to
increases in BMD in postmenopausal women
with osteoporosis. Although increased BMD is
independently associated with a reduced risk of
fracture, it is critical that the new bone formed
297
Baseline
Mean % change
Month 6Month 3 Month 12
–100
–80
–60
–40
–20
0
–40%
–53%
p < 0.001
p
< 0.001
p
< 0.001
Alendronate 70 mg OW Risedronate 35 mg OW
A
lendronate n = 462 429
Risedronate n
= 457 449
414
426
365
375
Treatment difference 13%
Urine NTx
Baseline
Month 6Month 3 Month 12
–100
–80
–60
–40
–20
0
–55%
–74%
p < 0.001
p < 0.001
p
< 0.001
443
455
449
459
423
433
382
387
Treatment difference 19%
Serum CTx
Figure 8 Mean percentage changes from baseline of markers of bone resorption. OW, once weekly; NTx,
N-telopeptide; CTx, C-telopeptide
USE OF ALENDRONATE IN OSTEOPOROSIS TREATMENT
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during therapy is of normal quality to effect
greater strength and resistance to fracture. His-
tomorphometric studies have confirmed that bis-
phosphonate treatment produces new bone of
normal quality, with normal lamellar architec-
ture and mineralization. BPs work by decreasing
bone turnover, increasing bone mineral density
and strengthening bone, thus playing a vital role
in the reduction of fracture risk. Although bis-
phosphonates may have similar mechanisms of
action, the results of the FACT study show that
bisphosphonates are not equally effective.
Recently, a randomized, double-blind, multi-
center 12-month study has compared the effi-
cacy and tolerability of once-weekly (OW) alen-
dronate (ALN) 70 mg and raloxifene (RLX)
60 mg daily in the treatment of postmenopausal
osteoporosis
21
. In total, 456 postmenopausal
women with osteoporosis (223 ALN, 233 RLX)
were enrolled at 52 sites in the United States.
Efficacy measurements included lumbar spine
(LS), total hip and trochanter BMD at 6 and 12
months, biochemical markers of bone turnover
and percentage of women who maintained or
gained BMD in response to treatment. The pri-
mary end-point was percentage change from
baseline in spine BMD at 12 months. Adverse
experiences were recorded to assess treatment
safety and tolerability. Over 12 months, OW
ALN produced a significantly greater increase in
spine BMD (4.4%, p < 0.001 than did RLX
(1.9%). The percentages of women with ≥ 0%
increase in LS BMD (ALN 94%, RLX 75%;
p < 0.001) and ≥ 3% increase in LS BMD (ALN
66%, RLX 38%; p < 0.001) were significantly
greater with ALN than with RLX. Total hip and
trochanter BMD increases were also significantly
greater (p ≤ 0.001) with ALN. Greater
(p < 0.001) reductions in N-telopeptide of type I
collagen and bone-specific alkaline phosphatase
were achieved with ALN compared with RLX at
6 and 12 months. No significant differences in
the incidence of upper-gastrointestinal or vaso-
motor adverse experiences were seen.
Long-term efficacy of alendronate has also
been demonstrated in the prevention of bone loss
in early postmenopausal women. The Early Post-
menopausal Intervention Cohort (EPIC) study
22
enrolled 1609 women across four centers.
Women were 45–59 years old, in good general
health and at least 6 months postmenopausal at
baseline; 585 patients were randomized to
receive the same dose of alendronate (2.5 or 5 mg
daily) or placebo continuously for 6 years of the
298
Baseline
Mean % change
Month 6Month 3 Month 12
–100
–80
–60
–40
–20
0
–28%
–41%
p < 0.001
p
< 0.001
p
< 0.001
Alendronate 70 mg OW Risedronate 35 mg OW
A
lendronate n = 449 441
Risedronate n
= 458 454
422
430
382
387
Treatment difference 13%
Serum BSAP
Baseline
Month 6Month 3 Month 12
–100
–80
–60
–40
–20
0
–48%
–64%
p < 0.001
p
< 0.001
p
< 0.001
440
455
447
459
419
432
378
387
Treatment difference 16%
Serum PINP
Figure 9 Mean percentage changes from baseline of markers of bone formation. OW, once weekly; BSAP,
bone-specific alkaline phosphatase; PINP, N-terminal propeptide of type I procollagen
POSTMENOPAUSAL OSTEOPOROSIS
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study. Postmenopausal women treated with
placebo for 6 years experienced significant pro-
gressive decreases in BMD of the spine, hip, fore-
arm and total body (all p values < 0.001) (Figure
10). In contrast, women who received 6 years of
treatment with alendronate (2.5 or 5 mg daily)
experienced significant gains versus baseline val-
ues in mean lumbar spine, trochanter and total
hip BMD (p<0.001). A significant increase in
BMD at the femoral neck versus baseline values
(p < 0.01) was observed only in women who
received continuous 5 mg alendronate for 6
years.
Patients who received placebo for 6 years
experienced a small mean decrease in urinary
NTx levels (approximately 25% at 6 months)
followed by a progressive further decline until
approximately 3 years (Figure 11). The levels
remained relatively stable from then to the end
of 6 years, resulting in a final value 37.9% below
baseline.
In the groups receiving alendronate, 2.5 mg
and 5 mg daily for 6 years, there was a much
greater dose-related decrease in mean urinary
NTx during the first year of treatment followed
by a further small decline up to year 3, and then
it remained relatively stable within the normal
premenopausal range. At the end of 6 years, the
mean percentage changes from baseline were
-63.9 and -68.0% for the 2.5-mg and 5-mg alen-
dronate groups, respectively. The decreases in
bone resorption in the two alendronate groups
299
(a)
Years
0123456
–4
–3
–2
–1
0
1
2
3
4
5
Mean % change
(b)
Years
0123456
–4
–3
–1
0
1
3
4
5
Mean % change
(c)
Years
0123456
–4
–3
–2
1
0
1
5
Mean % change
(d)
Years
0123456
–6
–5
–4
–3
–2
–1
0
1
Mean % change
Figure 10 The Early Postmenopausal Intervention Cohort (EPIC) study. Both alendronate groups (2.5 mg
and 5 mg ) exhibited significantly larger bone mineral density (BMD) increases at the spine (a) and the hip (b)
at the end of 6 years compared with the placebo group ( ). Treatment with 5 mg alendronate also prevented
total body bone loss (c) and attenuated BMD loss at the forearm (d) when compared with placebo. Furthermore,
BMD increases were significantly larger for the 5-mg alendronate group compared with the 2.5-mg group,
except for the femoral neck
USE OF ALENDRONATE IN OSTEOPOROSIS TREATMENT
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in preventing bone loss both at the spine and the
hip
23
.
A 2-year double-blind trial was conducted,
aimed at assessing the effect of 10 mg daily of
alendronate on bone mineral density in 241 men
(aged 31–87 years, mean 63 years) with osteo-
porosis
24
. Approximately one-third had low
serum free-testosterone concentrations at base-
line. Men with other secondary causes of osteo-
porosis were excluded. Alendronate increased
BMD by 7.1% at the lumbar spine, 2.5% at the
femoral neck and 2.0% for the total body
(p < 0.001 for all comparisons with baseline).
Men who received placebo had an increase in
spine BMD of 1.8%, and no significant changes
in femoral neck or total body BMD. BMD
changes in the alendronate group were greater
than in the placebo group at all skeletal sites
(p < 0.001). New vertebral fracture incidence
was decreased by 89% in the alendronate group
(0.8% vs. 7.1% in placebo group, p = 0.02).
In conclusion, alendronate efficacy and safety
have been extensively verified by the longest
intervention trials available to date in prevention
and treatment of osteoporosis.
300
Years
0123456
–80
–70
–60
–50
–40
–30
–20
–10
0
Mean % change
Placebo ALN 2.5 mg ALN 5 mg
Figure 11 Mean percentage change in urinary
N-telopeptide (NTx) level
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POSTMENOPAUSAL OSTEOPOROSIS
were significantly (p < 0.001) different from the
placebo group at the end of year 6.
Alendronate efficacy has been elucidated also
in secondary osteoporosis. In corticosteroid-
induced osteoporosis, 2-year alendronate treat-
ment has been shown to be very effective in
reducing new vertebral fracture risk by 90% and
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