Note: Descriptions are shown in the official language in which they were submitted.
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METHOD FOR ELVHANCING BONE MINERAL DENSITY GAIN
BACKGROUND OF THE INVENTION
Current major diseases or conditions of bone which are
of public concern include post-menopausal osteoporosis,
senile osteoporosis, patients undergoing long-term treatment
with corticosteroids, patients suffering from Cushings's
syndrome, gonadal dysgenesis, periarticular erosions in
rheumatoid arthritis, osteoarthritis, hypercalcemia of
malignancy, osteopenia due to bone metastases, and
periodontal disease. All of these conditions are
charac-terized by bone loss, resulting from an imbalance
between the degradation of bone (bone resorption) and the
formation of new healthy bone. This turnover of bone.
continues normally throughout life and is the mechanism by
which bone repairs and remodels. However, the conditions
stated above may tip the balance towards bone loss such that
the amount of bone resorbed is inadequately replaced with
new bone, resulting in net bone loss.
One of the most common bone disorders is post-
menopausal osteoporosis which affects an estimated 20 to 25
million women in the United States alone. Women after
menopause experience an increase in the rate of bone
turnover with resulting net loss of bone, as circulating
estrogen levels decrease. The rate of bone turnover differs
between bones and is highest in sites enriched with
trabecular bone, such as the vertebrae and the proximal
femur. The potential for bone loss at these sites
immediately following menopause is up to 4-5% per year or
more. The resulting decrease in bone mass and enlargement
of bone spaces leads to increased fracture risk, as the
mechanical integrity of bone deteriorates.
At present, there are 20 million people with detectable
vertebral fractures due to osteoporosis and 250,000 hip
fractures per year attributable to osteoporosis in the U.S.
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The latter case is associated with a 12o mortality rate
within the first two years and 30o of the patients will
require nursing home care after the fracture. Therefore,
bone disorders are characterized by a noticeable mortality
rate, a considerable decrease in the survivor's quality of
life, and a significant financial burden to families and
society.
Essentially all of the conditions listed above would
benefit from treatment with agents which inhibit bone
resorption. Bone resorption proceeds by the activity of
specialized cells called osteoclasts. Osteoclasts are
unique in their ability to resort both the hydroxyapatite
mineral and organic matrix of bone. They are somewhat
similar to the cartilage resorting cells, termed
chondroclasts. Tt is for this reason that potent inhibitors
of osteoclastic bone resorption may also inhibit the cell-
mediated degradation of cartilage observed in rheumatoid
arthritis and osteoarthritis.
Therapeutic treatments to impede net bone loss include
the use of estrogens. Estrogens have been shown clearly to
arrest the bone loss observed after menopause and limit the
progression of osteoporosis; but patient compliance has been
poor because of estrogen side-effects. These side effects
include resumption of menses, mastodynia, increase in the
risk of uterine cancer, and possibly an increase in the risk
of breast cancer.
There are also a number of studies documenting the
effects of the simultaneous combination of various
antiresorptive agents. For example, the simultaneous
administration of estrogen and the bisposponate alendronate
has been shown to increase the bone mineral density (BMD)
effects of estrogen alone in postmenopausal women with
osteoporosis; Lindsay et al., J. Clin. Endacrinol. Metab.
84, 3076-3081 (1999). Similarly, a different
bisphosphonate, etidronate, has shown additive BMD effects
when administered concurrently with estrogens; Wimalawansa,
Am. J. Med. 104, 219-226 (1998). Further, raloxifene HCl, a
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selective estrogen receptor modulator (SERM), has recently
shown additive BNm effects during simultaneous treatment
with alendronate; Johnell et al., J. Bone Miner. Res. 14
(Suppl.l), 5157. However, the use of tamoxifen, another
SERM, in premenopausal women, who have substantial
endogenous estrogen levels, has resulted in reductions in
BMD; Powles et al., J. Clin. Oncol. 14, 78-84 (1996).
Therefore, the effect of two simultaneous antiresorptives is
not readily predictable.
Furthermore, pharmaceutical compositions containing a
bisphosphonate and an anti-resorptive agent for inhibiting
bone loss are disclosed in European Patent Application Publ.
No. 0 693 285 A2, inventors Black, L.J. and Cullinan, G.J.,
with a publication date of Jan. 24, 1996.
Third generation bisphosphonates such as alendronate
are potent inhibitors of bone resorption, resulting in
marked reductions in bone metabolic activity. Indeed,
alendronate, especially when co-administered with estrogen,
may result in suppression of bone turnover to levels that
are below the mean for normal premenopausal women; Lindsay
et al., J. Clin. Endocrinol. Metab. 84, 3076-3081 (1999).
Prolonged profound reduction in bone turnover could
theoretically result in an undesirable state of "frozen
bone," with reduction in bone formation and bone resorption
to such an extent that normal repair and rejuvenation could
become impaired. It is therefore desirable to find a bone
loss treatment regimen that gives rapid clinical response
without resulting in prolonged impairment of normal
maintenance systems.
The current invention invokes the sequential use of a
bisphosphonate followed by switching to raloxifene or
pharmaceutically acceptable salt or solvate thereof, for the
purpose of further increasing BMD in humans previously
treated with a bisphosphonate. This benefit on BNa7 is
associated with a shift of bone turnover markers back toward
normal levels, reducing the risks of "frozen bone" that may
be associated with excessive suppression of bone turnover by
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administration of highly potent antiresorptives either alone
or in combination.
Clinical data supporting this invention have been
collected. These data demonstrate that treatment with the
bisphosphonate alendronate,.for one year, followed
sequentially by raloxifene alone, surprisingly results in
further increases of BMD compared to alendronate followed by
placebo. At the same time, bone turnover markers either
return towards normal or remain suppressed but do not
further decrease in the sequentially treated subjects. This
surprising combination of effects, an increase BMD with
return towards normal or maintenance without further
suppression of bone turnover, makes this invention an ideal
bone loss treatment regimen.
SUMMARY OF THE INVENTION
This invention relates to a method for enhancing bone
mineral density gain acquired through previous
bisphosphonate therapy comprising administering to a human
in need thereof a bone-enhancing amount of raloxifene or a
pharmaceutically acceptable salt or solvate thereof.
Further, this invention relates to a method of
inhibiting bone loss in a human in need thereof comprising
administering a bone-enhancing amount of raloxifene or a
pharmaceutically acceptable salt or solvate thereof
subsequent to a course of bisphosphonate therapy.
This invention further relates to the use of raloxifene
or a pharmaceutically acceptable salt or solvate thereof, in
the preparation of a medicament for enhancing bone mineral
density gain in a human, wherein said bone mineral density
gain is acquired through previous bisphosphonate therapy.
In another embodiment, this invention relates to the
use of raloxifene or a pharmaceutically acceptable salt or
solvate thereof, in the preparation of a medicament for
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inhibiting bone loss in a human subsequent to a course of
bisphosphonate therapy.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "inhibit" is defined to
include its generally accepted meaning which includes
preventing, prohibiting, restraining, and slowing, stopping
or reversing progression, or severity, and holding in check
and/or treating existing characteristics. The present
method includes both medical therapeutic and/or prophylactic
treatment, as appropriate.
The phrase "enhance" is defined to include its
generally accepted meaning which includes increasing,
magnifying, amplifying, heightening, escalating, improving,
boosting, intensifying and augmenting. Rises or gains in
lumbar BI~'.m with biphosphonate therapy for osteoporosis are
generally in the range of four to eight percent compared to
baseline with a majority of this rise occurring during the
first twelve months of treatment. During the twelve months
following discontinuation of therapy, the BMD is either
generally stable or tending to decrease whereas markers of
bone turnover return toward baseline. Increases in BNm in
the order of 1-2% during the twelve months following
discontinuation of bisphosphonate therapy, as is shown in
the present invention, would be very much unexpected,
especially if the bone turnover markers were either stable
or returning toward baseline.
The phrase "bisphosphonate therapy" refers to
administration of an effective amount of a bisphosphonate
for a period of time sufficient to approach a plateau for
bone density effect. A preferred length of time for a
course of bisphosphonate therapy is at least six months,
including treatment for six months to three years,
preferably for at least about one year, with discontinuation
of the therapy when appropriate to avoid excessive bone
turnover.
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The term "BMD" refers to bone mineral density.
The term "salt" or "pharmaceutically acceptable salt"
refers to salts of the compounds of the above classes that
are substantially non-toxic to living organisms. Typical
pharmaceutically acceptable salts include those salts
prepared by reaction of a compound of the above class with a
pharmaceutically acceptable mineral or organic acid, or a
pharmaceutically acceptable alkali metal or organic base,
depending on the types of~substituents present on the
compound.
Examples of pharmaceutically acceptable mineral acids
which may be used to prepare pharmaceutically acceptable
salts include hydrochloric acid, phosphoric acid, sulfuric
acid, hydrobromic acid, hydroiodic acid, phosphorous acid
and the like. Examples of pharmaceutically acceptable
organic acids which may be used to prepare pharmaceutically
acceptable salts include aliphatic mono and dicarboxylic
acids, oxalic acid, carbonic acid, citric acid, succinic
acid, phenyl-substituted alkanoic acids, aliphatic and
aromatic sulfonic acids and the like. Such pharmaceutically
acceptable salts prepared from mineral or organic acids thus
include hydrochloride, hydrobromide, nitrate, sulfate,
pyrosulfate, bisulfate, sulfite, bisulfate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, hydroiodide, hydrofluoride, acetate,
propionate, formate, oxalate, citrate, lactate, p-
toluenesulfonate, methanesulfonate, maleate, and the like.
Many compounds of the above classes which contain a
carboxy, carbonyl, or hydroxy or sulfoxide group may be
converted to a pharmaceutically acceptable salt by reaction
with a pharmaceutically acceptable alkali metal or organic
base. Examples of pharmaceutically acceptable organic bases
which may be used to prepare pharmaceutically acceptable
salts include ammonia, amines such as triethanolamine,
triethylamine, ethylamine, and the like. Examples of
pharmaceutically acceptable alkali metal bases included
compounds of the general formula MOZ, where M represents an
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alkali metal atom, e.g. sodium, potassium, or lithium, and Z
represents hydrogen or C1-C4 alkyl, wherein C1-C4 alkyl
represents a straight or branched chain alkyl radical of one
to four carbon atoms such as methyl, ethyl, propyl,
isopropyl and the like.
It should be recognized that the particular anion or
ration forming a part of any salt of this invention is not
critical, so long as the salt, as a whole, is
pharmacologically acceptable and as long as the anion or
cationic moiety does not contribute undesired qualities.
In addition, some of the compounds disclosed as useful
in the methods of the present invention may form solvates
with water or common organic solvents. Such solvates are
included within the scope of the present invention and
solvates thereof.
The class of compounds known as bisphosphonates
includes those compounds which contains a di-phosphoniC acid
moiety separated by a carbon link and include a variety of
side-chains, usually containing a basic function. The
compounds have the following general structure:
o~ ooY
P-OY
R1 R~
P
~O ~~OY
O OY
Y, R1 and R2 may be those substitutents as defined in US
Patent 5,139,786, and EPO Publication 0416689A2, published
March 13, 1991, incorporated herein by reference, although
not limited to such. A variety of bisphosphonic acids have
been disclosed as being useful in the treatment and
prevention of diseases involving bone resorption.
Representative examples may be found in the following: U.S.
Pat. Nos. 3,962,432, 4,054,598, 4,267,108, 4,327,039,
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4,621,077, 4,624,947, 4,746,654, and 4,922,077, each of
which is incorporated by reference herein as if fully set
forth.
Pharmacologically, these compounds have been shown to
slow or stop bone resorption by inhibiting osteoclast cell
function. Several compounds of this class are currently
undergoing clinical evaluation for the treatment of post-
menopausal osteoporosis. Many of these compounds are also
being evaluated for the treatment of Paget's Disease and
hypercalcemia malignancy and several have been approved.
The art refers to three different generations of
bisphosphonates. The first generation usually refers to the
compound etidronate. This compound is being marketed for
the treatment of Paget's disease and hypercalcemia
malignacy.
The second generation of bisphosphonates refers to the
compounds clodronate and pamidronate. Clodronate and
pamidronate are both is marketed for Paget's disease and
hypercalcemia maligancy. Pamidronate will probably be
approved for osteoporosis in some European countries in the
near future.
The third generation of bis-phosphonates refer to
alendronate, residronate, and tiludronate and a host of
lesser known compounds. Pharmacologically, these compounds
are much more potent and are claimed to have fewer side-
ef fects .
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The structures of some bisphosphonate compounds are as
follows
~~ /OH
P~
OH Cycloheptylaminomethylidene
NH H Bis Phosphonate Sodium Salt
,OH
P~
O ONa
~~ /OH
P
OOH
C OH Risedronate
OH 3-Pyridenylmethyl-1-Hydroxymethylide
N //P\ Bisphosphonate Sodium Salt
O ONa
~~ OOH
P
OOH Clodronate
C CI Dichloromethylidene Bis Phosphonate
~O H
/~P~
O OH
~~ SOH
P~
OH
H2NCHzC OH Pamidronate
OOH 3-Amino-1-Hydroxypropylidene
//P\ Bis Phosphonate
O OH
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~\ /OH
P~
OH Etidronate
CH OH 1-Hydroxyethylidene Bis Phosphonate
~O H
/j \
O OH
~\ /OH
POOH Alendronate
H2NCH2CH2CH2 OH 4-Amino-1-Hydroxybutylidene Bis Phosphonat
OOH Sodium Salt
P\
O ONa
~\ OOH
P~
OH .
H2NCH2CH2CH2CH2CH OH 6-Amino-1-Hydroxyhexylidene
OOH Bis Phosphonate Sodium Salt
//P\
O ONa
~\ OOH
P~
OH
CI \ ~ -S H Tiludronate
,OH 4-Chloropenylthiomethylidene
/ P\ Bis Phosphonate
O / OH
~\ /OH
P~
\ OH 3-Pyrolidenyl-1-Hydroxypropylidene
N-CH2CH2 /O OH Bis Phosphonate
O OH
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While some bisphosphonates are indicated for treating
osteoporosis; they also appear to have potential detrimental
side-effects. For example, bisphosphonates have the
potential of inhibiting bone formation as well as
resorption; they are poorly adsorbed via oral administration
and are known to cause gastrointestinal irritation; they
have extremely long half-lives in bone; they may all have
the potential for causing osteomalacia; and there is concern
as to the bio-mechanical strength of the bones treated with
bisphosphonates.
During a course of bisphosphonate therapy, the amount
of bisphosphonate administered to adult humans ranges from
about 1 mg/day to about 400 mg/day. A course of
bisphosphonate therapy generally lasts until a BMD plateau
is achieved although such therapy may be used for repeated
courses or continuously for an indefinite time. A preferred
length of time for a course of bisphosphonate therapy is for
at least about six months, including treatment for six
months to three years, preferably for at least about one
year, with discontinuation of the therapy when appropriate
to avoid excessive suppression of bone turnover.
Preferred bisphosphonates are alendronate and
risedronate, and salts thereof. Alendronate sodium is sold
commercially as FOSAMAX~. Alendronate and salts thereof may
be prepared according to known procedures such as those
detailed in U.S. Pat. Nos. 4,621,077, 5,358,941, 5,681,590,
5,804,570, 5,849,726, and 6,008,207, each of which is
incorporated by reference herein as if fully set forth.
Risedronate sodium is sold commercially as ACTONEL~.
Risedronate and salts thereof may be prepared according to
known procedures such as those detailed in U.S. Pat. No.
5,583,122, herein incorporated by reference as if fully set
forth.
The particular dosage of a bisphosphonate required to
approach BNa7 plateau according to this invention will depend
upon the particular circumstances of the conditions to be
treated. Generally, an effective minimum daily dose for
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alendronate sodium is about 1, 2.5, 5, 10 or 20 mg.
Typically, an effective maximum daily dose is about 200,
100, 80, 60 or 40 mg. A preferred daily dosage range is
from about 5 mg to about 10 mg per day. For treatment of
osteoporosis in postmenopausal women, the most preferred
dosage is 10 mg once a day. For prevention of osteoporosis
in postmenopausal women, the most preferred dosage is 5 mg
once a day. For the treatment of glucocorticoid-induced
osteoporosis in men and women, the most preferred dosage is
5 mg once a day, except for postmenopausal women not
receiving estrogen, for whom the most preferred dosage is 10 .
mg once per day. For the treatment of Paget's disease of
bone in men and women, the most preferred treatment regimen
is 40 mg once a day for six months.
For risedronate, the preferred daily dose is about 1,
2.5, 5, 10, 15, or 30 mg. Typically, an effective maximum
daily dose is about 300, 150, 120, 90, or 60 mg. For
treatment of osteoporosis in postmenopausal women, the most
preferred dosage ranges from about 2.5 to 20 mg per day,
with 5 mg once per day being preferred. For the treatment
of Paget's disease of bone in men and women, the most
preferred treatment regimen is 30 mg once a day.
However, it will be understood that the amount of the
bisphosphonate actually administered will be determined by a
physician in light of the relevant circumstances including
the condition to be treated, the choice of compounds to be
administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms
and the chosen route of administration.
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Raloxifene hydrochloride, which is 6-hydroxy-2-(4-
hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-
benzo[b]thiophene, is sold commercially as EVISTA~ and is
represented by the formula:
o ~ ~ o~ . HCi
N
S ~ ~ off
HO
Raloxifene and salts and solvates thereof may be prepared
according to known procedures, such as those detailed in
U.S. Pat. Nos. 4,133,814, 4,418,068, 5,631,369, 5,731,327,
1,0 5,731,342, 5,750,688 and 5,977,383, each of which is
incorporated by reference herein as if fully set forth.
Preferred crystalline forms, particle sizes and
pharmaceutical formulations are disclosed in U.S. Pat. Nos.
5,641,790, 5,731,327, 5,747,510, and 5,811,120, each of
which is incorporated by reference herein as if fully set
forth.
Pharmaceutical formulations can be prepared by
procedures known in the art, such as, for example, in
European Published Application 670162A1, published September
6, 1995, and in WO 97/35571 published October 2, 1997, both
of which are herein incorporated by reference. For example,
a compound of formula I can be formulated with common
excipients, diluents, or carriers, and formed into tablets,
capsules, and the like.
Examples of excipients, diluents, and carriers that are
suitable for formulation include the following: fillers and
extenders such as starch, sugars, mannitol, and silicic
derivatives; binding agents such as carboxymethyl cellulose
and other cellulose derivatives, alginates, gelatin, and
polyvinyl pyrrolidone; moisturizing agents such as
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glycerol; disintegrating agents such as agar, calcium
carbonate, and sodium bicarbonate; agents for retarding
dissolution such as paraffin; resorption accelerators such
as quaternary ammonium compounds; surface active agents such
as cetyl alcohol, glycerol monostearate; adsorptive carriers
such as kaolin and bentonire; and lubricants such as talc,
calcium and magnesium stearate and solid polyethyl glycols.
Final pharmaceutical forms may be: pills, tablets, powders,
lozenges,, syrups, aerosols, saches, cachets, elixirs,
suspensions, emulsions, ointments, suppositories, sterile
injectable solutions, or sterile packaged powders, depending
on the type of excipient used.
Additionally, raloxifene and its pharmaceutically
acceptable salts are suited to formulation as sustained
release dosage forms. The formulations can also be so
constituted that they release the active ingredient only or
preferably in a particular part of the intestinal tract,
possibly over a period of time. Such formulations would
involve coatings, envelopes, or protective matrices which
may be made from polymeric substances or waxes.
The particular dosage of raloxifene or a
pharmaceutically acceptable salt thereof required to
constitute a "bone-enhancing amount" according to this
invention will depend upon the particular circumstances of
the conditions to be treated. Considerations such as
dosage, route of administration, and frequency of dosing are
best decided by the attending physician. Generally, an
effective minimum dose for oral or parenteral administration
of raloxifene or a pharmaceutically acceptable salt thereof
is about 1, 5, 10, 15, or 20 mg. Typically, an effective
maximum dose is about 800, 120, 60, 50, or 40 mg. A
particularly effective amount is 60 mg of raloxifene
hydrochloride (56 mg of free base) per day via an oral route
of administration. Such dosages will be administered to a
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patient in need of treatment from one to three times each
day or as often as needed to effectively enhance bone
mineral density gain acquired through previous bisphoshonate
therapy. Raloxifene hydrochloride may be administered for
extended periods of time including six months to two years,
specifically including about one year. Raloxifene
hydrochloride may be used for repeated courses or
continuously for an indefinite time.
The formulations which follow are given for purposes of
illustration and are not intended to be limiting in any way.
The total active ingredient in such formulations comprises .
from 0.1% to 99.9% by weight of the formulation. The term,
"active ingredient" means a compound of formula I, or a
pharmaceutical salt or solvate thereof, (preferably
raloxifene hydrochloride). An even more preferred
formulation of a compound of formula I would be raloxifene
hydrochloride in the particular crystalline form, particle
size, and composition illustrated in U.S. Pat. No. 5,731,327
and PCT application WO 97/35571 (2 October 1997) the
teachings of each are incorporated by reference.
Formulation 1
Gelatin Capsules
Ingredient Quantity (mg/capsule)
Active Ingredient 50-600
Starch NF 0-500
Starch flowable powder 0-500
Silicone fluid 350 centistrokes 0-15
The ingredients are blended, passed through a No. 45
mesh U.S. sieve, and filled into hard gelatin capsules.
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Formulation 2
Tablets
Ingredient Quantity (mg/tablet)
Active Ingredient 50-600
Starch 10-50
Cellulose, microcrystalline 10-20
Polyvinylpyrrolidone 5
(as 10% solution in water)
Sodium carboxymethyl cellulose 5
Magnesium stearate 1
Talc 1-5
The active ingredient, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The
solution of polyvinylpyrrolidone is mixed with the resultant
powders which are then passed through a No. l4 mesh U.S.
sieve. The granules thus produced are dried at 50-60° C and
passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl cellulose, magnesium stearate, and talc,
previously passed through a No. 60 mesh U.S. sieve, are °
added to the above granules and thoroughly mixed. The
resultant material is compressed in a tablet forming machine
to yield the tablets.
Formulation 3
Aerosol
Ingredient Weight o
Active Ingredient 0.50
Ethanol 29.50
Propellant 22 70.00
(Chlorodifluoromethane)
The active ingredient is mixed with ethanol and the
mixture added to a portion of the propellant 22, cooled to
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-30°C and transferred to a filling device. The required
amount is then fed to a stainless steel container and
diluted with the remainder of the propellant. The valve
units are then fitted to the container.
Formulation 4
Suspension
Ingredient Weight/Volume
Active Ingredient 100 mg
Sodium carboxymethyl
cellulose 50 mg
Syrup 1.25 mL
Benzoic acid solution (0.1M) 0.10 mL
Flavor q.v.
Color q.v.
Purified water to total 5 mL
Suspensions each containing 100 mg of a compound of
formula I per 5 mL dose are prepared as follows: the active
ingredient is passed. through a No. 45 mesh U.S. sieve and
mixed with the sodium carboxymethyl cellulose and syrup to
form a smooth paste. The benzoic acid solution, flavor, and
color diluted in water are added and mixture stirred
thoroughly. Additional water is added to bring the entire
mixture to the required volume.
Example
A phase 3, multicenter, double-blind, placebo
controlled, randomized clinical trial was conducted.
Objectives of the trial included comparing the effects of 12
months treatment with raloxifene HCl (60 mg/day),
alendronate (10 mg/day), or the combination of the two
agents together.versus placebo on BMD at the lumbar spine
and at the hip and also metabolic markers of bone turnover.
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Additional objectives included comparing the effects of
raloxifene 60 mg/day versus placebo during a second year of
study on the offset of action of raloxifene or alendronate,
as assessed by these same efficacy parameters.
Subjects were eligible for the trial if they were
ambulatory postmenopausal women up to 75 years of age,
inclusive, and had femoral neck BNQ7 more than 2.0 standard
deviations below the mean peak bone mass for healthy
premenopausal women (i.e. T-score c -2.0). Subjects were
ineligible if they had less than five years life expectancy,
had current bone disorders (other than primary
osteoporosis), had known or suspected history of carcinoma
of the breast or other estrogen-dependent neoplasm, had
history of cancer within five years of study, had abnormal
uterine bleeding or endometrial thickness > 5mm by
ultrasonography, had history of deep venous thrombosis or
pulmonary embolism, had significant liver, kidney,
gastroesophageal or intestinal malaborptive disease or any
endocrine condition (other than type 2 diabetes or
hypothyroidism) requiring pharmacologic therapy, were
currently consuming excess of alcohol or drugs of abuse or
were. using or had recently received hormones or other
therapies for osteoporosis.
Three hundred thirty-one (331) subjects were randomly
assigned to one of four initial treatment groups: placebo,
raloxifene 60 mg/day, alendronate 10 mg/day or raloxifene
plus alendronate together. After one year of therapy all
subjects were re-randomized to receive either placebo or
raloxifene 60 mg/day for an additional year of study. All
subjects received approximately 500 mg of elemental calcium
plus 400-600 I.U. of vitamin D/day throughout the entire
study. Subjects were seen at three monthly intervals, at
which time assessment of medication compliance and adverse
events were recorded. In addition subjects had BNa7 and
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biochemical markers of bone turnover (including serum
osteocalcin) repeated at six monthly intervals. Additional
procedures included annual mammograms, physical examinations
and periodic assessments of health-related quality of life
as well as sensory and neuromuscular tests to assess risks
for falls.
Two hundred sixty-six (266) subjects completed the
first therapy phase of 12 months and entered the extension
phase. Among them, two hundred fifty-six (256) subjects
completed 24 months of study. Rates of discontinuation
during both study periods (0-12 months and 12-24 months)
were not statistically significantly different across the
four initial treatment group assignments. Comparing the
group of subjects who were assigned to alendronate during
year one and then randomly assigned to either raloxifene or
placebo in year two, results of lumbar spine BMD, total hip
BMD, femoral neck BMD, Serum Type I collagen fragment /
creatinine ratio, N-telopeptide / creatinine ratio, bone
specific alkaline phosphatase, and serum osteocalcin are
given in the following tables:
Table 1: Lumbar Spine BMD (Mean percentage change from
baseline)
Alendronate Placebo or
Treatment Raloxifene
Periods Treatment
Periods
Treatment
Group 6 months 12 months 18 months 24 months
Aln/Pbo 3.43% 4.98% 4.34% 4.53%
(n=35) (n=35) (n=34) (n=32)
Aln/Rlx 4.26% 4.61% 5.86% 6.20%
(n=29) (n=30) (n=29) (n=27)
''Time from study start
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Table 2: Lumbar Spine BMD (Mean percentage change from end
of 12 month alendronate treatment period)
Placebo
or Raloxifene
Treatment
Period
Treatment 18 months 24 months
Mean % p-Value' Mean % p-Value'
Change (between- Change (between-
group) group)
Aln/Pbo -0.220 0.024 -0.06% 0.031
(n=34) (n=32)
Aln/Rlx 0.38%' 1.480'
(n=29) (n=27)
''Time from study start
zBetween-group change tested by an ANOVA (analysis of
variance) method
3Statistically significant within group change tested by
Student's t-test (p<0.05)
Table 3: Total Hip BMD (Mean percentage change from
baseline)
Alendronate Placebo or
Treatment Raloxifene
Periods Treatment
Period
Treatment
Group 6 months 12 months 18 months 24 months
.
Aln/Pbo 3.29% 3.24% 3.580 3.260
(n=27) (n=27) (n=26) (n=24)
Aln/Rlx 1.780 1.840 2.090 2.92%
(n=24) (n=25) (n=24) (n=23)
''Time from study start
Table 4: Total Hip BMD (Mean percentage change from end of
12 month alendronate treatment period)
Placebo
or_ Raloxifene
Treatment
Period
Treatment 18 months 24 months
Mean % p-Value Mean
' p-Value
Change (between- Change
(between-
group) group)
Aln/Pbo 0.11% 0.794 -0.30% 0.028
(n=34) (n=32)
Aln/Rlx 0.270 1.08%'
(n=29) (n=27)
'Time trom study start
Between-group change tested by an ANOVA
3Statistically significant within group change tested by
Student's t-test (p<0.05)
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Table 5: Femoral Neck BMD (Mean percentage change from
baseline)
Alendronate Placebo or
Treatment Raloxifene
Periods Treatment
Periods
Treatment
Group 6 months 12 months 18 months 24 months
Aln/Pbo 2.71% 3.700 3.790 3.51%
(n=35) (n=35) (n=34) (n=31)
Aln/Rlx 2.37% 2.53% 2.56% 3.23%
(n=29) (n=30) (n=29) (n=28)
lTime from study start
Table 6: Femoral Neck BMD (Mean percentage change from end
of 12 month alendronate treatment period)
Placebo
or Raloxifene
Treatment
Period
Treatment 18 months 24 months
Mean % p-Value Mean o p-ValueG
Change (between- Change (between-
group) group)
Aln/Pbo -0.010 0.826 -0.38a 0.202
(n=34) (n=31)
Aln/Rlx 0.23% 0.78%
(n=29) (n=28)
lTime from study start
2Between-group change tested by an ANOVA
Table 7: Serum Type I Collagen Fragment/Creatinine ratio
(Median percentage change from baseline)
Alendronate Placebo or
Treatment Raloxifene
Periods Treatment
Periods
Treatment
Group 6 months 12 months 18 months 24 months
Aln/Pbo -73.2% -71.50 -44.0% -14.0%
(n=26) (n=23) (n=32) (n=30)
Aln/Rlx -74.2% -82.2% -57.4% -53.4%
(n=22) (n=21) (n=24) (n=24)
'Time trom study start
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Table 8: Serum Type I Collagen Fragment/Creatinine ratio
(Median percentage change from end of 12 month alendronate
treatment period)
Placebo
or Raloxifene
Treatment
Period
Treatment 18 months 24 months
Mean % p-Value' Mean % p-Value'
Change (between- Change (between-
group) group)
Aln/Pbo 161%' 0.458 3490' 0.243
(n=22) (n=19)
Aln/Rlx 113%' 157%'
(n=21) (n=20)
lTime from study start
2Between-group change tested by an ANOVA on rank-transformed
data
3Statistically significant within group change tested by
Wilcoxon Signed Rank test (p<0.05)
Table 9: N-telopeptide/Creatinine ratio (Median percentage
change from baseline)
Alendronate Placebo or
Treatment Raloxifene
Periods Treatment
Periods
Treatment
Group 6 months 12 months 18 months 24 months
Aln/Pbo -62.40 -60.1% -30.40 -9.1%
(n=34) (n=31) (n=32) (n=30)
Aln/Rlx -58.90 -63.1 0 -25.5% -38.5%
(n=29) (n=27) (n=27) (n=26)
''Time from study start
Table 10: N-telopeptide/Creatinine ratio (Median percentage
change from end of 12 month alendronate treatment period)
Placebo
or Raloxifene
Treatment
Period
Treatment 18 months 24 months
Mean o p-Value Mean o p-Value'
Change (between- Change (between-
group) group)
Aln/Pbo 90.3%' 0.398 131%' 0.156
(n=30) (n=28)
Aln/Rlx 56.7% 39.6%
(n=26) (n=25)
''Time from study start
2Between-group change tested by an ANOVA on rank-transformed
data
3Statistically significant within group change tested by
Wilcoxon Signed Rank t-test (p<0.05)
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Table 11: Bone specific alkaline phosphatase (Median
percentage change from baseline)
Alendronate Placebo or
Treatment Raloxifene
Periods Treatment
Periods
Treatment
Group 6 months 12 months 18 months 24 months
Aln/Pbo -57.9% -53.40 -45.50 -39.50
(n=32) (n=31) (n=30) (n=28)
Aln/Rlx -60.0% -53.9% -45.0% -42.7%
(n=28) (n=27) (n=28) (n=27)
lTime from study start
Table 12: Bone specific alkaline phosphatase (Median
percentage change from end of 12 month alendronate treatment
period)
Placebo
or Raloxifene
Treatment
Period
Treatment 18 months 24 months
Mean % p-Value' Mean % p-Value'
Change (between- Change (between-
group) group)
Aln/Pbo 37 . 4 0 . 032 60 . 2 0' 0 . 013
0'
(n=30) (n=28)
Aln/Rlx 6 . 7 7 . 10
0
(n=27) (n=26)
''Time from study start
Between-group change tested by an ANOVA on rank-transformed
data
3Statistically significant within group change tested by
Wilcoxon Signed Rank t-test (p<0.05)
Table 13: Serum Osteocalcin (Median percentage change from
baseline)
Alendronate Placebo or
Treatment Raloxifene
Periods Treatment
Periods
Treatment
Group 6 months 12 months 18 months 24 months
Aln/Pbo -32.40 -45.4% -31.5% -25.5%
(n=33) (n=31) (n=30) (n=28)
Aln/Rlx -38.80 -42.3% -46.4% -40.8%
(n=28) (n=27) (n=28) (n=27)
lTime from study start
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Table 14: Serum Osteocalcin (Median percentage change from
end of 12 month alendronate treatment period)
Placebo
or Raloxifene
Treatment
Period
Treatment 18 months 24 months
Mean % p-Value'' Mean % p-Value'
Change (between- Change (between-
group) group)
Aln/Pbo 38.2%' <0.001 52.1%' <0.001
(n=30) (n=28)
Aln/Rlx -2.750 14.2%'
(n=27) (n=26) .
'Time from study start
ZBetween-group change tested by an ANOVA on rank-transformed
data
3Statistically significant within group change tested by
WilCOxon Signed Rank t-test (p<0.05)
