CLINICAL PHARMACOLOGY
Mechanism Of Action
Alendronate Sodium
Animal studies have indicated
the following mode of action. At the cellular level, alendronate shows
preferential localization to sites of bone resorption, specifically under
osteoclasts. The osteoclasts adhere normally to the bone surface but lack the
ruffled border that is indicative of active resorption. Alendronate does not
interfere with osteoclast recruitment or attachment, but it does inhibit
osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate
in bone showed about 10-fold higher uptake on osteoclast surfaces than on
osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate
administration in rats and mice, respectively, showed that normal bone was
formed on top of the alendronate, which was incorporated inside the matrix. While
incorporated in bone matrix, alendronate is not pharmacologically active. Thus,
alendronate must be continuously administered to suppress osteoclasts on newly
formed resorption surfaces. Histomorphometry in baboons and rats showed that
alendronate treatment reduces bone turnover (i.e., the number of sites at which
bone is remodeled). In addition, bone formation exceeds bone resorption at
these remodeling sites, leading to progressive gains in bone mass.
Cholecalciferol
Vitamin D3 is produced in the
skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by
ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D
3. In the absence of adequate sunlight exposure, vitamin D3 is an essential
dietary nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into
chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver. Conversion to
the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D3 (calcitriol) in
the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The
principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal
absorption of both calcium and phosphate as well as regulate serum calcium,
renal calcium and phosphate excretion, bone formation and bone resorption.
Vitamin D is required for
normal bone formation. Vitamin D insufficiency develops when both sunlight
exposure and dietary intake are inadequate. Insufficiency is associated with
negative calcium balance, increased parathyroid hormone levels, bone loss, and
increased risk of skeletal fracture. In severe cases, deficiency results in
more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness,
bone pain and osteomalacia.
Pharmacodynamics
Alendronate Sodium
Alendronate is a bisphosphonate
that binds to bone hydroxyapatite and specifically inhibits the activity of
osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with
no direct effect on bone formation, although the latter process is ultimately
reduced because bone resorption and formation are coupled during bone turnover.
Daily oral doses of alendronate
(5, 20, and 40 mg for six weeks) in postmenopausal women produced biochemical
changes indicative of dose-dependent inhibition of bone resorption, including
decreases in urinary calcium and urinary markers of bone collagen degradation
(such as deoxypyridinoline and crosslinked N-telopeptides of type I collagen).
These biochemical changes tended to return toward baseline values as early as 3
weeks following the discontinuation of therapy with alendronate and did not
differ from placebo after 7 months.
Long-term treatment of
osteoporosis with FOSAMAX 10 mg/day (for up to five years) reduced urinary
excretion of markers of bone resorption, deoxypyridinoline and cross-linked
N-telopeptides of type l collagen, by approximately 50% and 70%, respectively,
to reach levels similar to those seen in healthy premenopausal women. The
decrease in the rate of bone resorption indicated by these markers was evident
as early as one month and at three to six months reached a plateau that was
maintained for the entire duration of treatment with FOSAMAX. In osteoporosis
treatment studies FOSAMAX 10 mg/day decreased the markers of bone formation,
osteocalcin and bone specific alkaline phosphatase by approximately 50%, and
total serum alkaline phosphatase by approximately 25 to 30% to reach a plateau
after 6 to 12 months. Similar reductions in the rate of bone turnover were
observed in postmenopausal women during one-year studies with once weekly
FOSAMAX 70 mg for the treatment of osteoporosis. These data indicate that the
rate of bone turnover reached a new steady-state, despite the progressive
increase in the total amount of alendronate deposited within bone.
As a result of inhibition of bone resorption,
asymptomatic reductions in serum calcium and phosphate concentrations were also
observed following treatment with FOSAMAX. In the long-term studies, reductions
from baseline in serum calcium (approximately 2%) and phosphate (approximately
4 to 6%) were evident the first month after the initiation of FOSAMAX 10 mg. No
further decreases in serum calcium were observed for the five-year duration of
treatment; however, serum phosphate returned toward prestudy levels during
years three through five. In one-year studies with once weekly FOSAMAX 70 mg,
similar reductions were observed at 6 and 12 months. The reduction in serum
phosphate may reflect not only the positive bone mineral balance due to FOSAMAX
but also a decrease in renal phosphate reabsorption.
Osteoporosis in Men
Treatment of men with osteoporosis with FOSAMAX 10 mg/day
for two years reduced urinary excretion of cross-linked N-telopeptides of type
I collagen by approximately 60% and bone-specific alkaline phosphatase by
approximately 40%. Similar reductions were observed in a one-year study in men
with osteoporosis receiving once weekly FOSAMAX 70 mg.
Cholecalciferol
Vitamin D is required for normal bone formation. Vitamin
D insufficiency is associated with negative calcium balance, leading to
increased parathyroid hormone levels and worsening of bone loss associated with
osteoporosis. When taken without vitamin D, alendronate is also associated with
a reduction in serum calcium concentrations and increased parathyroid hormone
levels. In a 15-week trial, 717 postmenopausal women and men, mean age 67
years, with osteoporosis (lumbar spine bone mineral density [BMD] of at least
2.5 standard deviations below the premenopausal mean) were randomized to
receive either weekly FOSAMAX PLUS D 70 mg/2800 international units vitamin D
or weekly FOSAMAX 70 mg alone with no vitamin D supplementation. Patients who
were vitamin D deficient (25-hydroxyvitamin D less than 9 ng/mL) at baseline
were excluded. Treatment with FOSAMAX PLUS D 70 mg/2800 international units
resulted in a smaller reduction in serum calcium levels (-0.9%) when compared
to FOSAMAX 70 mg alone (-1.4%). As well, treatment with FOSAMAX PLUS D 70
mg/2800 international units resulted in a significantly smaller increase in
parathyroid hormone levels when compared to FOSAMAX 70 mg alone (14% and 24%,
respectively).
The sufficiency of patients' vitamin D status is best
assessed by measuring 25-hydroxyvitamin D levels. In the 15-week trial
mentioned above, baseline 25-hydroxyvitamin D levels were 22.2 ng/mL in the
FOSAMAX PLUS D group and 22.1 ng/mL in the FOSAMAX only group. After 15 weeks
of treatment, the mean levels were 23.1 ng/mL and 18.4 ng/mL in the FOSAMAX PLUS
D and FOSAMAX only groups, respectively. The final levels of 25-hydroxyvitamin
D at Week 15 are summarized in Table 4.
Table 4: 25-hydroxyvitamin D Levels after Treatment
with FOSAMAX PLUS D (70 mg/2800 international units) or FOSAMAX 70 mg at Week
15*
25-hydroxyvitamin D Ranges (ng/mL) |
Number (%) of Patients |
< 9 |
9-14 |
15-19 |
20-24 |
25-29 |
30-62 |
FOSAMAX PLUS D (70 mg/2800 international units) (N=357) |
4 (1.1) |
37 (10.4) |
87 (24.4) |
84 (23.5) |
82 (23.0) |
63 (17.7) |
FOSAMAX 70 mg (N=351) |
46 (13.1) |
66 (18.8) |
108 (30.8) |
58 (16.5) |
37 (10.5) |
36 (10.3) |
* Patients who were vitamin D
deficient (25-hydroxyvitamin D less than 9 ng/mL) at baseline were excluded. |
Patients (n=652) who completed
the above 15-week trial continued in a 24-week extension in which all received
FOSAMAX PLUS D (70 mg/2800 international units) and were randomly assigned to
receive either additional once weekly vitamin D3 2800 international units
(Vitamin D3 5600 international units group) or matching placebo (Vitamin D3 2800
international units group). After 24 weeks of extended treatment (Week
39 from original baseline), the mean levels of 25-hydroxyvitamin D were 27.9
ng/mL and 25.6 ng/mL in the vitamin D3 5600 international units group and
vitamin D3 2800 international units group, respectively. The percentage of
patients with hypercalciuria at Week 39 was not statistically different between
treatment groups.
The distribution of the final levels of 25-hydroxyvitamin
D at Week 39 is summarized in Table 5.
Table 5: 25-hydroxyvitamin D
Levels after Treatment with FOSAMAX PLUS D at Week 39
25-hydroxyvitamin D Ranges (ng/mL) |
Number (%) of Patients |
< 9 |
9-14 |
15-19 |
20-24 |
25-29 |
30-59 |
FOSAMAX PLUS D (Vitamin D3 5600 international units group)* (N=321) |
0 |
10 (3.1) |
29 (9.0) |
79 (24.6) |
87 (27.1) |
116 (36.1) |
FOSAMAX PLUS D (Vitamin D3 2800 international units group)†(N=320) |
1 (0.3) |
17 (5.3) |
56 (17.5) |
80 (25.0) |
74 (23.1) |
92 (28.8) |
* Patients received FOSAMAX 70
mg or FOSAMAX PLUS D (70 mg/2800 international units) for the 15-week base
study followed by FOSAMAX PLUS D (70 mg/2800 international units) and 2800 international
units additional vitamin D3 for the 24-week extension study.
† Patients received FOSAMAX 70 mg or FOSAMAX PLUS D (70 mg/2800 international
units) for 15-week base study followed by FOSAMAX PLUS D (70 mg/2800
international units) and placebo for the additional vitamin D3 for 24-week
extension study. |
Pharmacokinetics
Absorption
Alendronate Sodium
Relative to an intravenous
reference dose, the mean oral bioavailability of alendronate in women was 0.64%
for doses ranging from 5 to 70 mg when administered after an overnight fast and
two hours before a standardized breakfast. Oral bioavailability of the 10-mg
tablet in men (0.59%) was similar to that in women when administered after an
overnight fast and 2 hours before breakfast.
In a study, the alendronate in
the FOSAMAX PLUS D (70 mg/2800 international units) tablet and the FOSAMAX
(alendronate sodium) 70-mg tablet were found to be equally bioavailable. In a
separate study, the alendronate in the FOSAMAX PLUS D (70 mg/5600 international
units) tablet was found to be equally bioavailable to the alendronate in the
FOSAMAX (alendronate sodium) 70-mg tablet.
A study examining the effect of
timing of a meal on the bioavailability of alendronate was performed in 49
postmenopausal women. Bioavailability was decreased (by approximately 40%) when
10 mg alendronate was administered either 0.5 or 1 hour before a standardized
breakfast, when compared to dosing 2 hours before eating. In studies of
treatment and prevention of osteoporosis, alendronate was effective when
administered at least 30 minutes before breakfast.
Bioavailability was negligible
whether alendronate was administered with or up to two hours after a
standardized breakfast. Concomitant administration of alendronate with coffee
or orange juice reduced bioavailability by approximately 60%.
Cholecalciferol
Following administration of
FOSAMAX PLUS D (70 mg/2800 international units) after an overnight fast and two
hours before a standard meal, the baseline adjusted mean area under the
serum-concentrationtime curve (AUC 0-120 hrs ) for vitamin D3 was 120.7
ng-hr/mL. The baseline adjusted mean maximal serum concentration (C max ) of
vitamin D3 was 4.0 ng/mL, and the baseline adjusted mean time to maximal serum
concentration (T max ) was 10.6 hrs. The bioavailability of the 2800
international units vitamin D3 in FOSAMAX PLUS D is similar to 2800
international units vitamin D3 administered alone.
In a separate study, the
baseline adjusted mean AUC 0-80 hrs and baseline adjusted mean C max for
vitamin D3 were 355.6 ng-hr/mL and 10.8 ng/mL, respectively. The baseline
adjusted mean T max was 9.2 hrs. The bioavailability of the 5600 international
units vitamin D3 in the FOSAMAX PLUS D is similar to 5600 international units
vitamin D3 administered as two 2800 international units vitamin D3 tablets.
Distribution
Alendronate Sodium
Preclinical studies (in male
rats) show that alendronate transiently distributes to soft tissues following 1
mg/kg intravenous administration but is then rapidly redistributed to bone or
excreted in the urine. The mean steady-state volume of distribution, exclusive
of bone, is at least 28 L in humans. Concentrations of drug in plasma
following therapeutic oral doses are too low (less than 5 ng/mL) for analytical
detection. Protein binding in human plasma is approximately 78%.
Cholecalciferol
Following absorption, vitamin D3 enters the blood as
part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver
where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form.
Lesser amounts are distributed to adipose tissue and stored as vitamin D3 at
these sites for later release into the circulation. Circulating vitamin D3 is
bound to vitamin D-binding protein.
Metabolism
Alendronate Sodium
There is no evidence that alendronate is metabolized in
animals or humans.
Cholecalciferol
Vitamin D3 is rapidly metabolized by hydroxylation in the
liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to
1,25-dihydroxyvitamin D3, which represents the biologically active form.
Further hydroxylation occurs prior to elimination. A small percentage of
vitamin D3 undergoes glucuronidation prior to elimination.
Excretion
Alendronate Sodium
Following a single intravenous dose of [14C]alendronate,
approximately 50% of the radioactivity was excreted in the urine within 72
hours and little or no radioactivity was recovered in the feces. Following a
single 10-mg intravenous dose, the renal clearance of alendronate was 71 mL/min
(64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed
200 mL/min. Plasma concentrations fell by more than 95% within 6 hours
following intravenous administration. The terminal half-life in humans is
estimated to exceed 10 years, probably reflecting release of alendronate from
the skeleton. Based on the above, it is estimated that after 10 years of oral
treatment with FOSAMAX (10 mg daily) the amount of alendronate released daily
from the skeleton is approximately 25% of that absorbed from the
gastrointestinal tract.
Cholecalciferol
When radioactive vitamin D3 was intravenously
administered to healthy subjects, the mean urinary excretion of radioactivity
after 48 hours was 2.4% of the administered dose, and the mean fecal excretion
of radioactivity after 48 hours was 4.9% of the administered dose. In both
cases, the excreted radioactivity was almost exclusively as metabolites of the
parent. The mean half-life of baseline adjusted vitamin D3 in the serum
following an oral dose of FOSAMAX PLUS D is approximately 14 hours.
Specific Populations
Gender: Bioavailability and the fraction of an
intravenous dose of alendronate excreted in urine were similar in men and
women.
Geriatric: Alendronate Sodium
Bioavailability and disposition of alendronate (urinary
excretion) were similar in elderly and younger patients. No dosage adjustment
of alendronate is necessary.
Cholecalciferol
Dietary requirements of vitamin D3 are increased in the
elderly.
Race: Pharmacokinetic differences due to race have
not been studied.
Renal Impairment:
Alendronate Sodium
Preclinical studies show that, in rats with kidney
failure, increasing amounts of drug are present in plasma, kidney, spleen, and
tibia. In healthy controls, drug that is not deposited in bone is rapidly
excreted in the urine. No evidence of saturation of bone uptake was found after
3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male
rats. Although no formal renal impairment pharmacokinetic study has been
conducted in patients, it is likely that, as in animals, elimination of alendronate
via the kidney will be reduced in patients with impaired renal function.
Therefore, somewhat greater accumulation of alendronate in bone might be
expected in patients with impaired renal function.
No dosage adjustment is necessary for patients with creatinine
clearance 35 to 60 mL/min. FOSAMAX PLUS D is not recommended for patients with
creatinine clearance less than 35 mL/min due to lack of experience with
alendronate in renal failure.
Cholecalciferol
Patients with renal insufficiency will have decreased
ability to form the active 1,25-dihydroxyvitamin D3 metabolite.
Hepatic Impairment:
Alendronate Sodium
As there is evidence that alendronate is not metabolized
or excreted in the bile, no studies were conducted in patients with hepatic
impairment. No dosage adjustment is necessary.
Cholecalciferol
Vitamin D3 may not be adequately absorbed in patients
who have malabsorption due to inadequate bile production.
Drug Interactions
Alendronate Sodium
Intravenous ranitidine was shown to double the
bioavailability of oral alendronate. The clinical significance of this
increased bioavailability and whether similar increases will occur in patients
given oral H2-antagonists is unknown.
In healthy subjects, oral prednisone (20 mg three times
daily for five days) did not produce a clinically meaningful change in the oral
bioavailability of alendronate (a mean increase ranging from 20 to 44%).
Products containing calcium and other multivalent cations
are likely to interfere with absorption of alendronate.
Cholecalciferol
Olestra, mineral oils, orlistat, and bile acid
sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of
vitamin D. Anticonvulsants, cimetidine, and thiazides may increase the
catabolism of vitamin D.
Animal Toxicology And/Or Pharmacology
The relative inhibitory activities on bone resorption and
mineralization of alendronate and etidronate were compared in the Schenk assay,
which is based on histological examination of the epiphyses of growing rats. In
this assay, the lowest dose of alendronate that interfered with bone
mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose.
The corresponding ratio for etidronate was one to one. These data suggest that
alendronate administered in therapeutic doses is highly unlikely to induce
osteomalacia.
Clinical Studies
Treatment Of Osteoporosis In Postmenopausal Women
FOSAMAX Daily
The efficacy of FOSAMAX 10 mg daily was assessed in four
clinical trials. Study 1, a three-year, multicenter, double-blind,
placebo-controlled, US clinical study enrolled 478 patients with a BMD T-score
at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a
three-year, multicenter, double-blind, placebo-controlled, Multinational
clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5
with or without a prior vertebral fracture; Study 3, the Three-Year Study of
the Fracture Intervention Trial (FIT), a study which enrolled 2027
postmenopausal patients with at least one baseline vertebral fracture; and
Study 4, the Four-Year Study of FIT, a study which enrolled 4432 postmenopausal
patients with low bone mass but without a baseline vertebral fracture.
Effect on Fracture Incidence
To assess the effects of FOSAMAX on the incidence of
vertebral fractures (detected by digitized radiography; approximately one third
of these were clinically symptomatic), the U.S. and Multinational studies were
combined in an analysis that compared placebo to the pooled dosage groups of
FOSAMAX (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for
one year). There was a statistically significant reduction in the proportion of
patients treated with FOSAMAX experiencing one or more new vertebral fractures
relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk
reduction). A reduction in the total number of new vertebral fractures (4.2 vs.
11.3 per 100 patients) was also observed. In the pooled analysis, patients who
received FOSAMAX had a loss in stature that was statistically significantly
less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm).
The Fracture Intervention Trial (FIT) consisted of two
studies in postmenopausal women: the Three-Year Study of patients who had at
least one baseline radiographic vertebral fracture and the Four-Year Study of
patients with low bone mass but without a baseline vertebral fracture. In both
studies of FIT, 96% of randomized patients completed the studies (i.e., had a
closeout visit at the scheduled end of the study); approximately 80% of
patients were still taking study medication upon completion.
Fracture Intervention Trial: Three-Year Study (Patients With At Least One Baseline Radiographic Vertebral Fracture)
This randomized, double-blind, placebo-controlled,
2027-patient study (FOSAMAX, n=1022; placebo, n=1005) demonstrated that
treatment with FOSAMAX resulted in statistically significant reductions in
fracture incidence at three years as shown in Table 6.
Table 6: Effect of FOSAMAX
on Fracture Incidence in the Three-Year Study of FIT (patients with vertebral
fracture at baseline)
|
Percent of Patients |
FOSAMAX
(n=1022) |
Placebo
(n=1005) |
Absolute Reduction in Fracture Incidence |
Relative Reduction in Fracture Risk % |
Patients with: |
Vertebral fractures (diagnosed by X-ray)* |
≥ 1 new vertebral fracture |
7.9 |
15.0 |
7.1 |
47† |
≥ 2 new vertebral fractures |
0.5 |
4.9 |
4.4 |
90† |
Clinical (symptomatic) fractures |
Any clinical (symptomatic) fracture |
13.8 |
18.1 |
4.3 |
26‡ |
≥ 1 clinical (symptomatic) vertebral fracture |
2.3 |
5.0 |
2.7 |
54§ |
Hip fracture |
1.1 |
2.2 |
1.1 |
51¶ |
Wrist (forearm) fracture |
2.2 |
4.1 |
1.9 |
48¶ |
*Number evaluable for vertebral
fractures: FOSAMAX, n=984; placebo, n=966
†p < 0.001, ‡p=0.007, §p < 0.01, ¶p < 0.05 |
Furthermore, in this population
of patients with baseline vertebral fracture, treatment with FOSAMAX
significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%).
In the Three-Year Study of FIT,
fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11
(1.1%) of 1022 patients on FOSAMAX, p=0.047. Figure 1 displays the cumulative
incidence of hip fractures in this study.
Figure 1: Cumulative Incidence of Hip Fractures in the
Three-Year Study of FIT (patients with radiographic vertebral fracture at
baseline)
Fracture Intervention Trial: Four-Year Study (Patients With Low Bone Mass But Without A Baseline Radiographic Vertebral Fracture)
This randomized, double-blind,
placebo-controlled, 4432-patient study (FOSAMAX, n=2214; placebo, n=2218)
further investigated the reduction in fracture incidence due to FOSAMAX. The
intent of the study was to recruit women with osteoporosis, defined as a
baseline femoral neck BMD at least two standard deviations below the mean for
young adult women. However, due to subsequent revisions to the normative values
for femoral neck BMD, 31% of patients were found not to meet this entry
criterion and thus this study included both osteoporotic and non-osteoporotic
women. The results are shown in Table 7 below for the patients with
osteoporosis.
Table 7: Effect of FOSAMAX
on Fracture Incidence in Osteoporotic* Patients in the Four-Year Study of FIT
(patients without vertebral fracture at baseline)
|
Percent of Patients |
FOSAMAX
(n=1545) |
Placebo
(n=1521) |
nts Absolute Reduction in Fracture Incidence |
Relative Reduction in Fracture Risk (%) |
Patients with: |
Vertebral fractures (diagnosed by X-ray)† |
≥ 1 new vertebral fracture |
2.5 |
4.8 |
2.3 |
48‡ |
≥ 2 new vertebral fractures |
0.1 |
0.6 |
0.5 |
78§ |
Clinical (symptomatic) fractures |
Any clinical (symptomatic) fracture |
12.9 |
16.2 |
3.3 |
22¶ |
≥ 1 clinical (symptomatic) vertebral fracture |
1.0 |
1.6 |
0.6 |
41 (NS)# |
Hip fracture |
1.0 |
1.4 |
0.4 |
29 (NS)# |
Wrist (forearm) fracture |
3.9 |
3.8 |
-0.1 |
NS# |
*Baseline femoral neck BMD at least 2 SD below the mean
for young adult women
†Number evaluable for vertebral fractures: FOSAMAX, n=1426; placebo, n=1428
‡p < 0.001, §p=0.035, ¶p=0.01 # Not
significant. This study was not powered to detect differences at these sites. |
Fracture Results Across Studies
In the Three-Year Study of FIT,
FOSAMAX reduced the percentage of women experiencing at least one new radiographic
vertebral fracture from 15.0% to 7.9% (47% relative risk reduction,
p < 0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8%
to 2.1% (44% relative risk reduction, p=0.001); and in the combined
U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction,
p=0.034).
FOSAMAX reduced the percentage of women experiencing
multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative
risk reduction, p < 0.001) in the combined U.S./Multinational studies and from
4.9% to 0.5% (90% relative risk reduction, p < 0.001) in the Three-Year Study
of FIT. In the Four-Year Study of FIT, FOSAMAX reduced the percentage of
osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1%
(78% relative risk reduction, p=0.035).
Thus, FOSAMAX reduced the incidence of radiographic
vertebral fractures in osteoporotic women whether or not they had a previous
radiographic vertebral fracture.
Effect on Bone Mineral Density
The bone mineral density efficacy of FOSAMAX 10 mg once
daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar
spine bone mineral density [BMD] of at least 2 standard deviations below the
premenopausal mean) was demonstrated in four double-blind, placebo-controlled
clinical studies of two or three years' duration.
Figure 2 shows the mean increases in BMD of the lumbar
spine, femoral neck, and trochanter in patients receiving FOSAMAX 10 mg/day
relative to placebo-treated patients at three years for each of these studies.
Figure 2
 |
At three years significant
increases in BMD, relative both to baseline and placebo, were seen at each
measurement site in each study in patients who received FOSAMAX 10 mg/day.
Total body BMD also increased significantly in each study, suggesting that the
increases in bone mass of the spine and hip did not occur at the expense of
other skeletal sites. Increases in BMD were evident as early as three months
and continued throughout the three years of treatment. (See figure 3 for lumbar
spine results.) In the two-year extension of these studies, treatment of 147
patients with FOSAMAX 10 mg/day resulted in continued increases in BMD at the
lumbar spine and trochanter (absolute additional increases between years 3 and
5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm
and total body were maintained. FOSAMAX was similarly effective regardless of
age, race, baseline rate of bone turnover, and baseline BMD in the range
studied (at least 2 standard deviations below the premenopausal mean).
Figure 3
In patients with postmenopausal
osteoporosis treated with FOSAMAX 10 mg/day for one or two years, the effects
of treatment withdrawal were assessed. Following discontinuation, there were no
further increases in bone mass and the rates of bone loss were similar to those
of the placebo groups.
Bone Histology
Bone histology in 270
postmenopausal patients with osteoporosis treated with FOSAMAX at doses ranging
from 1 to 20 mg/day for one, two, or three years revealed normal mineralization
and structure, as well as the expected decrease in bone turnover relative to
placebo. These data, together with the normal bone histology and increased bone
strength observed in rats and baboons exposed to long-term alendronate
treatment, support the conclusion that bone formed during therapy with FOSAMAX
is of normal quality.
Effect on Height
FOSAMAX, over a three-or
four-year period, was associated with statistically significant reductions in
loss of height vs. placebo in patients with and without baseline radiographic
vertebral fractures. At the end of the FIT studies, the between-treatment group
differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year
Study.
FOSAMAX Once-Weekly
The therapeutic equivalence of
once-weekly FOSAMAX 70 mg (n=519) and FOSAMAX 10 mg daily (n=370) was
demonstrated in a one-year, double-blind, multicenter study of postmenopausal
women with osteoporosis. In the primary analysis of completers, the mean
increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%;
95% CI) in the 70-mg once-weekly group (n=440) and 5.4% (5.0, 5.8%; 95% CI) in
the 10-mg daily group (n=330). The two treatment groups were also similar with
regard to BMD increases at other skeletal sites. The results of the
intention-to-treat analysis were consistent with the primary analysis of
completers.
Concomitant Use with Estrogen
Hormone Replacement Therapy
The effects on BMD of treatment
with FOSAMAX 10 mg once daily and conjugated estrogen (0.625 mg/day) either
alone or in combination were assessed in a two-year, double-blind,
placebo-controlled study of hysterectomized postmenopausal osteoporotic women
(n=425). At two years, the increases in lumbar spine BMD from baseline were
significantly greater with the combination (8.3%) than with either estrogen or
FOSAMAX alone (both 6.0%).
The effects on BMD when FOSAMAX
was added to stable doses (for at least one year) of HRT (estrogen ± progestin)
were assessed in a one-year, double-blind, placebo-controlled study in
postmenopausal osteoporotic women (n=428). The addition of FOSAMAX 10 mg once
daily to HRT produced, at one year, significantly greater increases in lumbar
spine BMD (3.7%) vs. HRT alone (1.1%).
In these studies, significant
increases or favorable trends in BMD for combined therapy compared with HRT
alone were seen at the total hip, femoral neck, and trochanter. No significant
effect was seen for total body BMD.
Histomorphometric studies of
transiliac biopsies in 92 subjects showed normal bone architecture. Compared to
placebo there was a 98% suppression of bone turnover (as assessed by
mineralizing surface) after 18 months of combined treatment with FOSAMAX and
HRT, 94% on FOSAMAX alone, and 78% on HRT alone. The long-term effects of
combined FOSAMAX and HRT on fracture occurrence and fracture healing have not
been studied.
Treatment To Increase Bone Mass In Men With Osteoporosis
The efficacy of FOSAMAX in men with hypogonadal or
idiopathic osteoporosis was demonstrated in two clinical studies.
FOSAMAX Daily
A two-year, double-blind, placebo-controlled, multicenter
study of FOSAMAX 10 mg once daily enrolled a total of 241 men between the ages
of 31 and 87 (mean, 63). All patients in the trial had either a BMD T-score
less than or equal to -2 at the femoral neck and less than or equal to -1 at
the lumbar spine, or a baseline osteoporotic fracture and a BMD T-score less
than or equal to -1 at the femoral neck. At two years, the mean increases
relative to placebo in BMD in men receiving FOSAMAX 10 mg/day were significant
at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter,
3.1%; and total body, 1.6%. Treatment with FOSAMAX also reduced height loss
(FOSAMAX, -0.6 mm vs. placebo, -2.4 mm).
FOSAMAX Once-Weekly
A one-year, double-blind, placebo-controlled, multicenter
study of once weekly FOSAMAX 70 mg enrolled a total of 167 men between the ages
of 38 and 91 (mean, 66). Patients in the study had either a BMD T-score less
than or equal to -2 at the femoral neck and less than or equal to -1 at the
lumbar spine, or a BMD T-score less than or equal to -2 at the lumbar spine and
less than or equal to -1 at the femoral neck, or a baseline osteoporotic
fracture and a BMD T-score less than or equal to -1 at the femoral neck. At one
year, the mean increases relative to placebo in BMD in men receiving FOSAMAX 70
mg once weekly were significant at the following sites: lumbar spine, 2.8%;
femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in
BMD were similar to those seen at one year in the 10 mg once-daily study.
In both studies, BMD responses were similar regardless of
age (greater than or equal to 65 years vs. less than 65 years), gonadal
function (baseline testosterone less than 9 ng/dL vs. greater than or equal to
9 ng/dL), or baseline BMD (femoral neck and lumbar spine T-score less than or
equal to -2.5 vs. greater than -2.5).