CLINICAL PHARMACOLOGY
Mechanism Of Action
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.
Pharmacodynamics
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.
Osteoporosis In Postmenopausal Women
Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The
diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of
osteoporotic fracture, or height loss or kyphosis, indicative of vertebral (spinal) fracture. Osteoporosis
occurs in both males and females but is most common among women following the menopause, when
bone turnover increases and the rate of bone resorption exceeds that of bone formation. These changes
result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age
50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age
90, the risk of hip fracture in white women increases 50-fold and the risk of vertebral fracture 15- to
30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more
osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures,
in particular, are associated with substantial morbidity, disability, and mortality.
Daily oral doses of alendronate sodium (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 cross-linked 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 alendronate sodium 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. Similar decreases were seen in patients in osteoporosis prevention
studies who received alendronate sodium 5 mg/day. The decrease in the rate of bone resorption
indicated by these markers was evident as early as 1 month and at 3 to 6 months reached a plateau that
was maintained for the entire duration of treatment with alendronate sodium. In osteoporosis treatment
was maintained for the entire duration of treatment with alendronate sodium. In osteoporosis treatment
studies alendronate sodium 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. In osteoporosis prevention studies
alendronate sodium 5 mg/day decreased osteocalcin and total serum alkaline phosphatase by
approximately 40% and 15%, respectively. Similar reductions in the rate of bone turnover were
observed in postmenopausal women during one-year studies with once weekly alendronate sodium 70
mg for the treatment of osteoporosis and once weekly alendronate sodium 35 mg for the prevention 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 alendronate sodium. 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 alendronate sodium 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. Similar reductions were
observed with alendronate sodium 5 mg/day. In one-year studies with once weekly alendronate sodium
35 and 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 alendronate sodium but also a decrease in
renal phosphate reabsorption.
Osteoporosis In Men
Treatment of men with osteoporosis with alendronate sodium 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 alendronate sodium 70 mg.
Pharmacokinetics
Absorption
Relative to an intravenous (IV) 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.
BINOSTO 70 mg effervescent tablet and alendronate sodium 70 mg tablet are bioequivalent.
A study evaluating the effect of food on the bioavailability of BINOSTO was performed in 119 healthy
women. Bioavailability was decreased (by approximately 50%) when 70 mg alendronate sodium was
administered 15 minutes before a standardized breakfast, when compared to dosing 4 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 sodium was administered with or up to 2 hours after
a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced
bioavailability by approximately 60%.
Distribution
Preclinical studies (in male rats) show that alendronate sodium transiently distributes to soft tissues
following 1 mg/kg IV 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%.
Metabolism
There is no evidence that alendronate sodium is metabolized in animals or humans.
Excretion
Following a single IV 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 IV 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 IV 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 alendronate sodium (10 mg daily) the amount of alendronate
released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract.
Specific Populations
Gender
Bioavailability and the fraction of an intravenous dose excreted in urine were similar in men and
women.
Geriatric
Bioavailability and disposition (urinary excretion) were similar in elderly and younger
patients. No dosage adjustment is necessary in elderly patients.
Race
Pharmacokinetic differences due to race have not been studied.
Renal Impairment
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. BINOSTO is
not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience
with alendronate in renal failure.
Hepatic Impairment
As there is evidence that alendronate is not metabolized or exreted in the bile, no
studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary.
Drug Interactions
Ranitidine
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.
Prednis One
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%).
Calcium And Multivalent Cations
Products containing calcium and other multivalent cations are likely
to interfere with absorption of alendronate.
Levothyroxine
The geometric mean AUC(0-∞) and Cmax of alendronate decreased by 7% (point
estimate: 0.93; 90% CI: 0.79-1.08) and 9% (point estimate: 0.91; 90% CI: 0.77-1.08), respectively,
when a single dose of BINOSTO (70 mg alendronate) and 600 mcg levothyroxine were given
concomitantly to 29 healthy male and female subjects.
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
BINOSTO (alendronate sodium) effervescent tablet 70 mg is bioequivalent to alendronate sodium tablet
70 mg. The fracture reduction efficacy and bone mineral density changes attributed to BINOSTO are
based on clinical trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly.
Daily Dosing
The efficacy of alendronate sodium 10 mg daily was assessed in four clinical trials. Study 1, a threeyear,
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 alendronate sodium 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 alendronate sodium (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
alendronate 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 alendronate 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 (alendronate, n=1022; placebo,
n=1005) demonstrated that treatment with alendronate sodium resulted in statistically significant
reductions in fracture incidence at three years as shown in Table 4.
Table 4 Effect of Alendronate Sodium on Fracture Incidence in the Three-
Year Study of FIT (Patients With Vertebral Fracture at Baseline)
|
Percent of Patients |
Alendronate
Sodium
(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: alendronate, 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 alendronate
sodium 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 alendronate sodium, 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 (alendronate, n=2214; placebo,
n=2218) further investigated the reduction in fracture incidence due to alendronate sodium. 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 5 for the patients with osteoporosis.
Table 5 Effect of Alendronate on Fracture Incidence in Osteoporotic*
Patients in the Four-Year Study of FIT (Patients Without Vertebral Fracture
at Baseline)
|
Percent of Patients |
Alendronate
Sodium
(n=1545) |
Placebo
(n=1521) |
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: alendronate, 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, alendronate sodium 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).
Alendronate sodium 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, alendronate sodium reduced the percentage of
osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk
reduction, p=0.035).
Thus, alendronate sodium 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 alendronate sodium 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 4 double-blind, placebocontrolled
clinical studies of 2 or 3 years’ duration.
Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients
receiving alendronate sodium 10 mg/day relative to placebo-treated patients at three years for each of
these studies.
Figure 2 : Osteoporosis Treatment Studies in Postmenopausal Women Increase in BMD Alendronate Sodium 10 mg/day at Three Years
 |
At 3 years significant increases in BMD, relative both to baseline and placebo, were seen at each
measurement site in each study in patients who received alendronate 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 3 months and
continued throughout the 3 years of treatment. (See figures below for lumbar spine results.) In the 2-year
extension of these studies, treatment of 147 patients with alendronate sodium 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. Alendronate sodium 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 : Osteoporosis Treatment in Studies in Postmenopausal Women Time Course Effects of Alendronate Sodium 10 mg/day Versus Placebo: Lumbar Spine BMD Percent Change From Baseline
In patients with postmenopausal osteoporosis treated with alendronate sodium 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 alendronate sodium 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
alendronate sodium is of normal quality.
Effect on height
Alendronate sodium, 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.
Weekly Dosing
The therapeutic equivalence of once weekly alendronate sodium 70 mg (n=519) and alendronate sodium
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 1 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 2 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.
Treatment To Increase Bone Mass In Men With Osteoporosis
The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was
demonstrated in two clinical studies.
Daily Dosing
A two-year, double-blind, placebo-controlled, multicenter study of alendronate sodium 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: 1) 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 2) 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 alendronate
sodium 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 alendronate sodium also reduced height loss
(alendronate, -0.6 mm vs. placebo, -2.4 mm).
Weekly Dosing
A one-year, double-blind, placebo-controlled, multicenter study of once weekly alendronate sodium 70
mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had
either: 1) 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, 2) 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 3) 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
alendronate sodium 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 alendronate sodium 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).