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Time (months)
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Time (months)
Mean change in BMD from baseline (%)
Lumbar spine
all women
Femoral neck
all women
Lumbar spine
T-score below –1
Femoral neck
T-score below –1
A BC
1–2/5
2/5
1/2.5
1/5
Time (years)
End of studyBaseline 1 2 3 4 5 6 7 8
10
8
6
4
2
0
Mean change in BMD from baseline (%)
Figure 3 Bone mineral density (BMD) change (%) at the lumbar spine (L2–L4) from baseline until 9 years
284
POSTMENOPAUSAL OSTEOPOROSIS
Figure 2 Mean changes (%) in lumbar and femoral bone mineral density (BMD) after 4 years of treatment.
All women and women with low bone mass at baseline (BMD T-score below -1). Groups pooled according to
the estrogen dose regimen. Group A, 1–2 mg E
2
V (dose increased from 1 mg to 2 mg after 6 months); Group
B, 2 mg E
2
V; Group C, 1 mg E
2
V. MPA dose in all groups either 2.5mg or 5 mg. Figure reproduced with
permission from Osteoporosis International
3
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baseline values, and the changes remained signif-
icant at the 12-month and end-of-study measur-
ing points (Figure 7).
In group A (low turnover), no statistically
significant responses to treatment at 12 months
(PINP, p = 0.626; lumbar spine BMD, p =
0.117) were found. PINP changed + 4.7%, from
29.7 to 31.1
µg/l (Figure 8) and lumbar BMD
changed + 0.7%, from 1.171 to 1.180 g/cm
2
(Figure 9).
In women with high turnover (group B), sta-
tistically highly significant responses to treat-
ment at 12 months were found (PINP,
p < 0.0001; lumbar spine BMD, p < 0.0001).
1–2/5
2/5
1/2.5
1/5
Time (years)
End of studyBaseline 1 2 3 4 5 6 7 8
4.5
3.5
4
2.5
3
2.5
1
2
0.5
0
Mean change in BMD from baseline (%)
Figure 4 Bone mineral density (BMD) change (%) at the femoral neck from baseline to 9 years
Mean change in BMD from baseline (%)
12
8
10
6
4
2
1–2/5 2/5 1/5 1/2.5
0
Lumbar spine
Femoral neck
Trochanter
Ward's triangle
Figure 5 Increases in bone mineral density (BMD) (%) after 9 treatment years in lumbar spine, femoral neck,
Ward’s triangle and trochanter
285
EFFECT OF CONTINUOUS COMBINED HRT ON BONE AND BONE MARKER PINP
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PINP changed –49.1%, from 54.8 to 27.9 µg/l
(Figure 8), and lumbar spine BMD increased
5.1%, from 0.996 to 1.047 g/cm
2
(Figure 9).
When an increase of 2% in lumbar spine
BMD was considered a reliable sign of response,
18 of 22 in group A and only four of 22 in group
B exceeded this limit, leading to 81.8% sensitiv-
ity and 81.8% specificity at the cut-off of 40
µg/l
of baseline PINP.
Occurrence of fractures and overall
safety
The occurrence of fractures was very low in this
study: five foot or leg fractures, four radial and
two vertebral fractures. No hip fractures
occurred. All fractures occurred following an
accident, such as falling on an icy street, or car
accident. None of the women with fractures had
osteopenic or osteoporotic BMD.
286
Percentage of subjects
75
60
45
30
15
Baseline End of study
0
Normal
OsteoporoticOsteopenic
Figure 6 Proportion of women with normal bone mineral density (BMD), osteopenia or osteoporosis at
baseline and at 9 years
Time (months)
Baseline 3 months 6 months 12 months 108 months
45
30
15
0
PINP (µg/l)
42.23
41.42
33.45*
29.47*
32.2*
Figure 7 Serum N-terminal propeptide of type I procollagen (PINP) levels for subgroup receiving 1 + 2.5
regimen (n = 44) at baseline, 3 months, 6 months, 12 months and 9 years.
*
p <0.001
POSTMENOPAUSAL OSTEOPOROSIS
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Overall, all treatments had a favorable safety
profile with a low frequency of adverse drug reac-
tions or serious clinical outcomes, as reported in
the published article on 7-year results of this
study
4
.
CONCLUSIONS
Our results suggest that starting post-
menopausal hormone therapy with a lower estro-
gen dose and then increasing the dose after a few
months can be beneficial, especially for women
with low BMD. However, for most women, 1 mg
E
2
V dose level seems to be adequately effective in
the long-term prevention of postmenopausal
bone loss.
The baseline level of serum PINP is able to
predict skeletal response to low-dose HRT at
least at the 12-month time-point. The appropri-
ate cut-off level for baseline PINP was found to
be 40
µg/l in postmenopausal women. Only
those who are classified as ‘high bone turnover’
individuals show statistically significant BMD
increment and PINP decrease at the 12-month
time-point.
Based on these results, low-dose HRT can
still be regarded as a feasible option for the long-
term prevention of postmenopausal bone loss.
The final results of this study from the 10-
year measuring point, 1 year after discontinuing
HRT, will most probably shed more light on how
bone reacts to the stopping of long-term hor-
mone therapy and decreasing the estrogen dose
before ending therapy.
287
PINP (µg/l)
A PINP0 A PINP12 B PINP0 B PINP12
100
90
80
Group A: low
turnover
Group B: high
turnover
70
60
50
40
30
20
10
0
p < 0.0001
Figure 8 Serum N-terminal propeptide of type I
procollagen (PINP) at baseline and after 12 months of
treatment. Subgroups divided into women with low
(A) or high (B) bone turnover
BMD (g/cm
2
)
A BMD0 A BMD12 B BMD0 B BMD12
1.7
1.6
1.5
Group A: low turnover
Baseline PINP <
40 µg/l
Group B: high turnover
Baseline PINP > 40 µg/l
1.4
1.3
1.1
1.0
0.9
0.7
0.6
0.5
1.2
0.8
p < 0.001
Figure 9 Lumbar bone mineral density (BMD) at
baseline and at 12 months in N-terminal propeptide
of type I procollagen (PINP) subgroups A and B
EFFECT OF CONTINUOUS COMBINED HRT ON BONE AND BONE MARKER PINP
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1. Writing Group for the Women’s Health Initiative
Investigators. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women.
Principal results from the Women’s Health Ini-
tiative randomized controlled trial. J Am Med
Assoc 2002; 228: 321–33
2. North American Menopause Society. Estrogen
and progestogen use in peri- and postmenopausal
women: September 2003 position statement of
the North American Menopause Society.
Menopause 2003; 10: 497–506
3. Heikkinen J, Vaheri R, Kainulainen P, et al. Long-
term continuous combined hormone replacement
therapy in the prevention of postmenopausal
bone loss: a comparison of high- and low-dose
estrogen–progestin regimens. Osteoporos Int 2000;
11: 929–37
4. Heikkinen J, Vaheri R, Timonen U. Long-term
safety and tolerability of continuous-combined
hormone therapy in postmenopausal women:
results from a seven-year randomized comparison
of low and standard doses. J Br Menopause Soc
2004; 10: 95–102
288
References
POSTMENOPAUSAL OSTEOPOROSIS
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1 and 10%), which is probably paracellular
8
, and
the limited cellular uptake. Bisphosphonates are
rapidly excreted by the kidney, in part by an
active tubular secretion process
9
.
The key pharmacological action of bisphos-
phonates in clinical use is inhibition of bone
resorption. The mechanism of action of BPs has
not been fully elucidated, and could differ among
BPs. Since this is not the subject of this chapter,
it is suggested that the reader refers to a very
recent review
10
.
Sodium alendronate has been the first agent
to be developed according to US and European
regulatory guidelines for marketing authoriza-
tion of new agents for osteoporosis treatment.
Alendronate efficacy has been demonstrated in
terms of hard end-points, i.e. the reduction of
both new incident vertebral fractures and non-
vertebral fractures in patients with established
osteoporosis. In 1995, Liberman and colleagues
reported that alendronate increases bone mineral
density at the spine and hip as well as the whole
body, and reduces the risk of radiographically
defined vertebral fractures in women with low
bone mineral density (BMD)
11
.
The Fracture Intervention Trial (FIT) is unan-
imously considered a milestone in the history of
osteoporosis pharmacology; for the first time, a
randomized placebo-controlled trial was specifi-
cally designed for evaluating the efficacy of an
active drug, sodium alendronate, in reducing the
incidence of vertebral and non-vertebral fractures
in postmenopausal women with low bone mass,
with (n = 2027, vertebral deformity arm
12
) or
without (n = 4432, clinical fracture study
13
)
prevalent vertebral fractures at baseline.
In the first arm, 3-year alendronate treatment
of established osteoporosis reduced the risk of
The use of alendronate in osteoporosis
treatment: 10-year experience
M. L. Brandi
33
289
Bisphosphonates (BPs) are pyrophosphate
analogs in which the oxygen bridge has been
replaced by a carbon with various side-chains
(P–C–P). These compounds have been known to
chemists since the 19th century, the first synthe-
sis dating back to 1865
1
. They were first used in
various industrial procedures, among other
things as anticorrosive and antiscaling agents
2
.
After discovering that they can effectively con-
trol calcium phosphate formation and dissolution
in vitro, as well as mineralization and bone
resorption in vivo
3,4
, they were developed and
used in the treatment of metabolic bone diseases,
mostly Paget’s disease, hypercalcemia of malig-
nancy and, lately but not least, primary and sec-
ondary osteoporosis
5
.
The bisphosphonate group, like pyrophos-
phate, binds strongly to hydroxyapatite
6
. BPs
deposit where bone mineral is exposed to the sur-
rounding fluids, thus, especially where bone is
formed and resorbed. The release of bisphospho-
nates occurs primarily when the bone where they
are deposited is resorbed again, accounting for
their long in vivo half-life in humans
7
. The
P–C–P group is resistant to enzymatic hydroly-
sis, which explains why bisphosphonates are not
metabolized in the body and are excreted unal-
tered. Bisphosphonates released during bone
remodeling might therefore be pharmacologi-
cally active. The amount of bisphosphonate
released daily in this manner after 10 years of
treatment is estimated at ~ 25% of the amount
absorbed from a daily dose, and depends upon
the location in the skeleton. It will be higher for
cancellous, lower for compact bone. The charge
and bulk of the bisphosphonate group limits
penetration of cell membranes. This may account
for the low absorption in the gut (between below
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new morphometric vertebral fractures by 47%
and of clinical vertebral fractures by 55%. Wrist
fractures and hip fractures were also reduced
by alendronate treatment by 48% and 51%,
respectively.
In the clinical fracture arm, 4.25 years of
alendronate treatment reduced the risk of clinical
fractures by 36% and of newly diagnosed verte-
bral deformities by 50% in those women who
had a BMD T-score below –2.5, according to the
third National Health and Nutrition Examina-
tion Survey reference database.
A cumulative FIT database analysis evaluated
the efficacy of alendronate in osteoporosis
patients (existing vertebral fracture at baseline or
femoral neck T- score of 2.5 or less)
13
. Table 1
summarizes the key results.
Very recently, FIT 10-year follow-up study
(FLEX, FIT long-term extension) data were pub-
licly disclosed. FLEX is a randomized, double-
blind, placebo-controlled study aimed at assess-
ing the efficacy of continuing treatment with
alendronate (ALN) 5 or 10 mg/day (combined)
for an additional 5 years, versus discontinuing
therapy (i.e. placebo) in osteoporotic women pre-
viously treated with alendronate for ~ 5 years.
The primary objective was change in total hip
BMD. Secondary end-points were changes of
femoral neck, trochanter, spine and total body
BMD, and safety and tolerability data. As addi-
tional objectives, the study looked at the differ-
ent effects of ALN 5 and 10 mg/day on total hip,
femoral neck, trochanter, spine and total body
BMD, and resolution of the effect of prior
alendronate treatment on bone markers. The
incidence of clinical or morphometric vertebral
fractures compared with placebo was also
assessed as an exploratory objective.
The study enrolled 1099 postmenopausal
women previously enrolled in FIT and random-
ized to alendronate. Prior treatment with alen-
dronate was for 3 to ~ 6 years (average 5 years).
All patients had been treated for 3–4.25 years
during FIT and for 1–2 years of open-label alen-
dronate 10 mg/day after the end of FIT. Total hip
BMD T-score was above –3.5, and current total
hip BMD > total hip BMD at FIT baseline.
Patients were randomized to three arms: 437
patients were treated with placebo for 5 years;
329 and 333 patients received alendronate either
5 mg/day or 10 mg/day, respectively; and 995
patients completed the 5-year study and 759
women (69%) completed study therapy. The
baseline characteristics of the study population
are summarized in Table 2.
Both alendronate 5 mg and 10 mg/day
dosages were effective in maintaining total hip,
femoral neck and femoral trochanter BMD,
which was decreased in the placebo group
(p < 0.001 for comparison between placebo
group and pooled alendronate groups at each
skeletal site). However, BMD levels were still
higher in the placebo group than at FIT baseline;
the latter observation allows exclusion of any
‘catch-up’ phenomenon loss at the hip.
Lumbar spine BMD was largely increased in
both ALN groups (+5.0% and +5.6% in 5-mg
and 10-mg/day groups) versus a slight increase
Table 1 Key results of alendronate efficacy in osteoporosis
Fracture class RR (95% CI) p Value
Radiologic vertebral 0.52 (0.42–0.66) 0.001
Multiple vertebral (radiologic) 0.13 (0.07–0.25) 0.001
Clinical vertebral 0.55 (0.36–0.82) 0.003
Any clinical 0.70 (0.59–0.82) 0.001
Non-vertebral 0.73 (0.61–0.87) 0.001
Non-vertebral (osteoporotic) 0.64 (0.51–0.80) 0.002
Hip 0.47 (0.26–0.79) 0.005
Wrist 0.70 (0.49–0.98) 0.038
RR, relative risk; CI, confidence interval
POSTMENOPAUSAL OSTEOPOROSIS
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which was still observed in the placebo group
(+1.5%, p < 0.001 for comparison between
placebo group and pooled treated groups).
Table 3 shows BMD changes at different
measurement sites in the three groups.
According to BMD figures, bone turnover
markers (urinary cross-linked N-telopeptides of
type I collagen (NTx) and serum bone alkaline
phosphatase) were stable in the actively treated
group, but they were statistically significantly
increased (~ 30%) in the placebo group. As
mentioned before, a pre-specified exploratory
analysis was conducted in order to assess the
incidence of clinical vertebral fractures in study
subjects. The risk of clinical vertebral fractures
was 54% lower in the alendronate than in the
placebo group (p = 0.01): 23 women experienced
clinical vertebral fractures (5.4%) in the placebo
group, compared with 16 women (2.5%) in the
pooled alendronate groups.
Overall safety was similar across groups.
Bone safety was also assessed by two-dimen-
sional (2-D) and 3-D evaluation of bone biopsy:
no qualitative abnormalities were observed at
both histologic and mineralization levels.
The FLEX data disclosure follows the recent
publication
14
of the 10-year follow-up data of
the alendronate phase III trial
11
. Initially, 994
291
Table 2 Baseline characteristics of study population in Fracture Intervention Trial (FIT) long-term extension
(FLEX)
ALN→PBO ALN→ALN 5 mg ALN→ALN 10 mg
Age (years) 74 73 73
Spine BMD (g/cm
2
) 0.90 0.90 0.89
T-score –1.6 –1.6 –1.7
Total hip BMD (g/cm
2
) 0.72 0.73 0.73
T-score –1.8 –1.7 –1.7
NTx (pmol/µmol creatinine) 23.5 22.4 22.3
BSAP (ng/ml) 9.7 9.3 9.5
Prevalent vertebral fractures (%) 32.2 29.5 31.5
Prevalent vertebral fractures 54.2 51.2 53.6
or hip BMD T-score < –2.5 (%)
BMD, bone mineral density; NTx, cross-linked N-telopeptides of type I collagen; BSAP, bone-specific alkaline
phosphatase; ALN, alendronate; PBO, placebo
Table 3 Bone mineral density changes (%) in three study groups
Site ALN→PBO ALN→ALN 5 mg ALN→ALN 10 mg
Total hip –3.4
***
–1.3
***
–0.7
**
Femoral neck –1.5
**
0.1 0.9
*
Trochanter –3.3
***
–0.2 0.1
Lumbar spine 1.5
***
5.0
***
5.6
***
Total body –0.3 0.6
*
1.5
***
To tal forearm –3.2
***
–0.9
**
–1.5
***
*
p ≤ 0.05 vs. baseline;
**
p ≤ 0.01 vs. baseline;
***
p ≤ 0.001 vs. baseline; ALN, alendronate; PBO, placebo
USE OF ALENDRONATE IN OSTEOPOROSIS TREATMENT
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women had been randomly assigned to receive 5,
10 or 20 mg of oral alendronate or placebo daily
(Figure 1). Women in the placebo group were
given open-label alendronate for years 4 and 5
and then discharged from the study. The original
5-mg and 10-mg alendronate groups continued
to receive the same doses in all three extensions
of the study (years 4 and 5, 6 and 7 and 8–10).
Those in the original 20-mg group received 5 mg
for years 3–5 and placebo for years 6–10 (the dis-
continuation group). Their cumulative exposure
to alendronate was similar to exposure in the 10-
mg group after 5 years, and to that in the 5-mg
group after 10 years. Both the investigators and
the women were aware that all long-term partic-
ipants had received alendronate for at least 5
years and that the discontinuation group had
been switched to placebo, but all remained
unaware of each woman’s current treatment.
The primary end-point was lumbar spine
BMD change. Secondary end-points were
changes in BMD at the hip (femoral neck,
trochanter, total proximal femur), total body and
forearm regions, and changes in the levels of
urinary NTx and serum bone-specific and total
alkaline phosphatase (ALP).
Lumbar spine BMD continued to increase
during years 6–10 and 8–10 in both alendronate
groups (Figure 2). The mean change after 10
years of the 10-mg daily dose was +13.7%,
compared with baseline; smaller changes were
observed in the 5-mg group. During years 6–10,
the alendronate groups had no significant decline
in BMD. In the discontinuation group, spine
BMD did not change significantly after year 5;
significant decreases occurred at the total hip,
femoral neck and forearm, but bone mineral den-
sity at the lumbar spine, trochanter, total hip and
total body remained significantly above basal
values at year 10. Almost 90% of women who
took the 10-mg dose daily had an increase in
total hip BMD.
The fast reduction of bone turnover back to
the premenopausal range which had been
observed after initial 3–6-month treatment was
sustained through 10 years of treatment. NTx
values declined by almost 66% at the end of year
10 (Figure 3). During years 8–10, urinary NTx
292
994 (804)
underwent randomization
199 (160)
assigned to 20 mg of
alendronate for years 1–2
and 5 mg for year 3
202 (164)
assigned to 5 mg of
alendronate
196 (158)
assigned to 10 mg of
alendronate
397 (322)
assigned to placebo
143 (114)
assigned to 5 mg of
alendronate
145 (112)
assigned to 5 mg of
alendronate
151 (120)
assigned to 10 mg of
alendronate
288 (232)
assigned to placebo
3-year study
1st extension,
years 4–5
2nd extension,
years 6–7
3rd extension,
years 8–10
83 (51.9% of 160)
assigned to placebo
78 (47.6% of 164)
assigned to 5 mg of
alendronate
86 (54.4% of 158)
assigned to 10 mg of
alendronate
115 (97)
assigned to 5 mg of
alendronate
113 (92)
assigned to 5 mg of
alendronate
122 (105)
assigned to 10 mg of
alendronate
Ineligible for
further study
Figure 1 Design of the alendronate phase III trial
POSTMENOPAUSAL OSTEOPOROSIS
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remained stable in the alendronate groups.
Serum bone-specific alkaline phosphatase levels
declined by 49% in the 10-mg group at the end
of year 10. After discontinuation of alendronate,
bone markers increased within 1 year, but they
still remained below baseline values.
Fracture incidence was evaluated for safety
purposes. During the initial 3-year study, 6.2%
of women in the placebo group had new mor-
phometric vertebral fractures, compared with
3.2% in the pooled alendronate groups
(p = 0.03). Proportions among the three alen-
dronate groups were similar. For this analysis,
228 women could be evaluated for years 6–10.
The incidence of new morphometric vertebral
fractures did not differ significantly among the
three groups. The rate of radiologically con-
firmed non-vertebral fractures in the 10-mg
group was similar to that in the pooled alen-
dronate groups during the first 3 years of the
study.
The latter and the FLEX trial both represent
the longest follow-up that has been extended to
date for assessing the long-term efficacy and
safety of an osteoporosis drug, i.e. alendronate, in
the treatment of postmenopausal osteoporosis.
Some concerns have been raised about the
long-term bone safety of continuous BP treat-
ment. The amount of BP retained in bone after
10 years of alendronate treatment was estimated
at 75 mg per 2 kg mineral, using a pharmaco-
kinetic model for a dose of 10 mg per day. This
293
Year
Change in lumbar spine BMD (%)
0
0
2
4
6
8
10
12
14
12345678910
Year
Change in total hip BMD (%)
0
0
1
3
2
4
5
6
7
8
9
123456789
10
Figure 2 Changes in lumbar spine and total hip bone
mineral density (BMD) in the 10-mg alendronate
group (square symbols), 5-mg alendronate group
(circle symbols) and discontinuation group (diamond
symbols)
Year
Change in urinary N-telopeptides
of type I collagen (%)
0
–90
–80
–70
–50
–60
–40
–30
–20
–10
0
123456789
10
Year
Change in bone-specific
alkaline phosphatase (%)
0
–70
–60
–50
–40
–30
–20
–10
0
12345678910
Figure 3 Changes in bone markers in the 10-mg
alendronate group (filled squares), 5-mg alendronate
group (filled circles), discontinuation group (filled
diamonds) and placebo group (open circles)
USE OF ALENDRONATE IN OSTEOPOROSIS TREATMENT
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