Note: Descriptions are shown in the official language in which they were submitted.
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TITL,E OF THE INVENTION
USE OF ALENDRONATE FOR THE PREVENTION OF
OST]_OPOROSIS
S FII~LD OF THE INVENTION
l[his invention relates to the use of alendronate, an amino-
bisphosphonate, for the prevention of osteoporosis in early post-
menopausal women.
BACKGROUND OF THE INVENTION
Alendronate, 4-amino- 1 -hydroxybutylidene- 1,1-
bisph~osphonic acid, and its pharmaceutically acceptable salts has been
found to be useful in the treatment of osteoporosis. Alendronate is a
specific inhibitor of bone resorption. It has a high affinity for bone
mi~neral and is taken up into the bone selectively where it inhibits
osteoclast activity. While alendronate has been shown to be useful in
restoring lost bone, there has been no indication that it can prevent the
loss of bone in otherwise healthy individuals.
Peak bone mass in women is achieved at around 30-35
years of age, after which bone mass is lost progressively throughout
life. The rate of loss is accelerated during the early post menopausal
peliod, especially at sites with a high component of trabecular bone.
The average woman probably has a greater than 40%
ch~mce of developing at least one osteoporotic fracture during her
lifetime. Osteoporotic fractures, especially of the hip, are associated
with a marked reduction in the quality of life and high cost of treatment.
The l:otal costs and morbidity associated with all osteoporotic fractures
are certain to subst~nti~lly exceed those of hip fracture alone, although
precise estimates are not available.
At the present time, the only approved therapy for
prevention of osteoporosis is estrogen replacement therapy. Along with
a plrevention of bone loss associated with reduced endogenous estrogen
prodllction, ~lmini~tration of estrogen can help reduce post menopausal
symptoms such as vasomotor instability, vaginal atrophy, and an
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improvement in the lipid profile with a probable reduction in
cardiovascular problems. However, at the doses commonly employed
for bone loss prevention, many women lose bone despite continued
treaLtment. Further, estrogen treatment is also associated with some
serious risks, including endometrial carcinoma, symptomatic gall
bladder disease, and a possible increase in the incidence of breast cancer.
Altlhough some of these risks can be lowered by addition of progestins
to the therapeutic regimen or by yearly endometrial biopsies, a large
proportion of women will not accept long-term estrogen treatment
mainly because of poor tolerability and safety concerns.
It would be desirable to have an agent which can prevent
osteoporosis which does not have the risks and possible side effects
associated with estrogen.
PE~CRIPTION OF THE ~VENTION
This invention relates to a method of preventing
osteoporosis in women having a normal bone mineral density
comprising ;~lministering a prophylactically effective amount of
alendronate or a pharmaceutically acceptable salt thereof for a sufficient
amount of time.
A further aspect of this invention is a method of reducing
the risk of fracture in women by ~clmini~tering a prophylactically
effective amount of alendronate or a pharmaceutically acceptable salt
thereof for a substantial period of time.
Yet another aspect of this invention is a method of
preventing osteoporosis in early postmenopausal women by
~lministering a prophylactically effective amount of alendronate or a
pharmaceutically acceptable salt thereof.
Im the absence of preventive treatment, the microstructure
30 of the bone deteriorates as bone loss progresses, leading to a decrease in
bone strength per unit bone mass. Prophylactic ~(lmini~tration of ~Jalemdronate has been found, in accordance with this invention, to
preserve normal microstructure and normal bone strength. Thus a
further aspect of this invention is a method of preserving normal bone
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microstructure and bone strength by ~lministering a prophylactically
,~ effective amount of alendronate or a pharmaceutically acceptable salt thereof.
As used throughout the specification and claims, the
5 following definitions will apply:
"Prophylactically effective amount": an amount of
alendronate or a pharmaceutically acceptable salt thereof which is
suffiicient to prevent osteoporosis in women not currently suffering
from osteoporosis. This amount may or may not be a pharrnaceutically
10 acceptable arnount, i.e. sufficient to treat osteoporosis, i.e. restore bone
mas,s in a patient who is currently suffering from osteoporosis.
"Substantial period of time": a sustained period, i.e. at least
about three years, and preferably longer.
"Osteoporosis": a condition wherein a person's bone
15 mineral density is more than about 2 standard deviations below the peak
bone mineral density.
"Early post-menopause": less than approximately five years
after a woman's menstrual periods have ceased.
Alendronate may be prepared according to any of the
processes described in U.S. Patents 5,019,651, 4,992,007, and U.S.
Application Serial No. 08/2~s6,151, filed August 4, 1994, each of which
is hereby incorporated by reference. The pharmaceutically acceptable
salts of alendronate include salts of alkali metals (e.g., Na, K), alkali
eartlh metals (e.g. Ca), salts of inorganic acids, such as HCI and salts of
orgcmic acids such as citric acid and amino acids. Sodium salt forms are
preferred, particularly the monosodium salt trihydrate form.
The compounds of the present invention can be
~1mini~tered in oral dosage forms such as tablets, capsules (each of
which includes sustained release or timed release forrnulations), pills,
~' po~ders, granules, elixirs, paste, tinctures, suspensions, syrups,
emulsions, and zydis. Likewise they may be ~lmini~tered in an
intr;~venous (bolus or infusion), intraperitoneal, subcutaneous, or
intramuscular form, all using forms well known to those of ordinary
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- 4 -
skill in the pharmaceutical arts. An effective but non-toxic amount of
the compound desired can be used as a osteoporosis-preventing agent.
The dosage regimen utilizing the claimed method is selected
in accordance with a variety of factors including age, weight, sex, and
5 meclical condition of the patient; the route of ~lministration; the renal
and hepatic function of the patient; and the particular compound or salt
thereof employed. An ordinarily skilled physician or clinician can
readily determine and prescribe the effective amount of the drug
re4uired to prevent osteoporosis.
Oral dosages of the present invention will range from
between 0.05 mg per kg of body weight per day (mglkg/day) to about
1.0 mg/kg/day. Preferred oral dosages in humans may range from daily
total dosages of about 2.5-20 mg/day over the effective treatment
period, and a preferred prophylactic amount is 2.5, 5, or 10 mg/day.
Alendronate may be 7~1ministered in a single daily dose or
in a divided dose. It is desirable for the dosage to be given in the
absence of food, preferably from about 30 minutes to 2 hours prior to a
meal, such as breakfast, to permit adequate absorption.
In the methods of the present invention, the active
20 ingredient is typically ~lmini~tered in admixture with suitable
pharmaceutical diluents, excipients or carriers (collectively referred to
herein as "carrier materials") suitably selected with respect to the
intended form of ~lmini~tration, i.e. oral tablets, capsules, elixirs,
syrups and the like and consistent with conventional pharmaceutical
25 practices. For example, for oral ~rlmini~tration in the form of a tablet
or capsule, the active ingredient can be combined with an oral, non-
toxic, pharmaceutically acceptable inert carrier such as lactose, starch,
sucrose, glucose, methyl cellulose, cros-carmellose sodium, magnesium
steaLrate, mannitol, sorbitol and the like; for oral allmini~tration in liquid
30 form, the oral drug components can be combined with any oral, non-
toxic, pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents and coloring agents
can also be incorporated into the mixture of active ingredient(s) and
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i~ ine~ carrier materials. Suitable binders may include starch, gelatin,natural sugars such as glucose, anhydrous lactose, free-flow lactose,
beta-lactose, and corn sweeteners, natural and synthetic gums, such as
acacia, tragacanth or sodium alginate, carboxymethyl cellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
A particularly preferred tablet formulation is that described in U.S.
Pa.tent 5,358,941, which is hereby incorporated by reference.
The compounds used in the instant method may also be
coupled with soluble polymers as targetable drug carriers. Such
polymers can include polyvinylpyrrolidone, pyran co-polymer,
polyhydroxylpropyl-methacrylamide and the like.
The following non-limiting examples are presented to
illustrate the invention.
EXAMPLE 1
Women enrolled in this study are in good general health
and are between 45-59 years old and have been selected randomly from
a target population who live in a defined geographical area. The
majority are early postmenopausal. Fewer than 15 percent of the
participants have any incidence of osteoporosis evident on baseline
spinal dual-energy X-ray densitometry.
Each subject is randomized to ether placebo, alendronate
lo~v dose (ALN 2.5 mg per day), alendronate high dose (ALN 5 Ing per
day) or open labeled estrogen/progestin (E/P). The estrogen/progestin
group (in the United States) will receive the conjugated estrogen
PREMARIN~) (0.625 mg per day) and the medroxyprogesterone acetate
PRCIVERA~) (S mg per day) taken continuously throughout the
calendar month. Outside the United States, the estrogen/progestin group
will receive micronized 17b-estradiol and norethisterone acetate
(Trisequens) as a cyclical regimen. All subjects who have a calcium
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intake of less than 500 mg per day will be advised to increase their
calcium intake (eithér by diet or supplements) to above this level. ,J
Dis~ribution of the groups is shown in TABLE 1. The duration of
treatment in each of the groups is given in TABLE 2.
TABLE 1
TREATMENT GROUPS
STRATUM I STRATUM 2
GROUP TREATMENT N N TOTAL
A Placebo 150 300 450
B ALN 2.5 mg 150 300 450
C ALN 5 mg 150 300 450
D E/P 150 -- 150
TOTAL 600 900 1500
ALN=Alendronate
E/P =Estrogen/Progestin
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~' TABLE 2
~t
STUDY SCHEMA
YEAR OF S~UDY
GROUP N 1 and 2 3 and 4 5 and 6
A 450 Placebo Placebo ALN OD; or
Placebo*
E~l 150 ALN 2.5 mg ALN 2.5 mg ALN 2.5 m~
B2 150 ALN 2.5 mg ALN 2.5 mg Placebo
E~3 150 ALN 2.5 mg Placebo
C1 150 ALN 5 mg ALN 5 mg ALN 5 mg
C2 150 ALN 5 mg ALN 5 mg Placebo
C3 150 ALN 5 mg Placebo
D 150 E/P E/P
5 ALN= Alendronate
OD= Optimal Dose (either 2.5 or 5 mg).
*Subsequent randomization for placebo group Years 5 and 6
extension
E,/P= Estrogen/Progestin
The study is double blind (for women receiving either
alendronate or placebo) for the first two years, at the end of which a
first analysis is performed. The study remains double blind until each
subject reaches the end of the fourth year of study, when the blind is
15 brok.en for each subject individually. Subjects are informed only
whether or not they received active treatment with alendronate, and, if
sc,, whether ~hey were treated for two or four years. Subjects w;ll not
be informed of the dose of the study drug. Those subjects who remain
in the blinded study for years 5 and 6, and the investigators remain
20 blinded to their treatment allocation during the extension period.
Subjects in Group "A" (See TABLE 2) continue to take
blinlded placebo for four years. At the end of four years these women
will be informed that they had received placebo during Years 1 to 4.
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They are then given the option to be further randomized ( 1:1 ) between
blinded placebo and alendronate and the "optimal" dose or to exit the y
.study.
Groups B 1 and C2 receive the 2.5 or 5 mg of alendronate,
respectively for six years. Groups B2 and C2 will remain on the 2.5
and 5 mg of alendronate, respectively for four years before switching to
placebo for the final two years of the study. Those subjects who remain
in the study for Years 5 and 6 will be blinded (double blind) regarding
their allocation to active drug or placebo for Years 5 and 6. Groups B3
and C3 remain on the 2.5 and 5 mg alendronate, respectively for only
two years before switching to placebo for the third and fourth years of
the study. They will discontinue study drug after the fourth year.
Subjects in Group D continue ~e open-label
estrogen/progestin treatment for four years, after which they will
discontinue the study drug after the fourth year.
After four years, women receiving alendronate are not
developing signs of osteoporosis, as measu~ed, e.g. by decreases in bone
mineral density, whereas those receiving placebo are experiencing a loss
in bone mineral density. The differences are statistically significant.
