Note: Descriptions are shown in the official language in which they were submitted.
CA 022234~0 1997-12-04
W O g6/39107 PCTrUS96/0851
TITLE OF THE INVENTION
BISPHOSPHONATE CEMENT COMPOSITION TO PREV~NT
~SEPTIC LOOSENING OF ORTHOPEDIC IMPLANT DEVICES
5 F~IELD OF THE ~NVENTION
The instant invention relates to the use of bisphosphonate
salts, e.g., alendronate, in an acrylate-based polymer bone cement
such as polymethylmethacrylate (PMMA), to prevent periprosthetic
bone loss and failure of a joint prosthesis and in arthroplasty patients
10 having an orthopedic implant device.
BACKGROUND OF THE INVENTION
There are approximately 300,000 prosthetic implants
performed per year on a world-wide basis, including hip and knee
15 implants. Of this population, there is about a 5-50% failure rate
within ten years of the operation, depending upon the specific type of
prosthesis, requiring a repeat surgery and device re-implant. This
failure rate increases exponentially with time so that many patients
with an aging prosthesis gradually experience pain at the site of the
20 implant and eventually require implant replacement. This condition
of pain is considered to be a result of fragmentation of the cement
substances utilized in hip prostheses, leading to macrophage-mediated
inflammation. Further, at the time these patients develop pain and
loosening of the joint, they also exhibit markedly increased bone
25 turnover, especially bone resorption, in the periprosthetic bone
immediately adjacent to the implant. Evidence for this bone
turnover can be seen from the fact that bone scanning agents, which
include bisphosphonates tagged with technetium, are often taken up at
very high concentrations in these areas of the periprosthetic bone.
30 Bone turnover in this instance, unfortunately, leads to a steady loss of
the supporting periprosthetic bone structure, aseptic (absence of
bacterial infection) loosening of the implant device and making
necessary replacement surgery. See J. Bone and Joint Surge~y, Vol.
CA 022234~0 1997-12-04
W O 96/39107 PCT~US96/08515
74-A, No. 6, pages 849-862 (July 1992) and Vol 75-A, No. 6 pages
802-813 (June 1993).
Applicants have discovered that this problem can be
overcome by incorporating a bone resorption inhibitor into the
5 implant cement, which binds (~lxates) the device to the supporting
trabecular or cortical bone in the cavity in which the bone is
inserted. The presence of a bone resorption inhibitor should
sufficiently inhibit bone resorption in the periprosthetic area of the
implant device to obviate replacement surgery.
Most of the currently new bone resorption inhibitors are
non-estrogenic therapeutic agents in the class of bisphosphonates.
These compounds are used in the treatment of osteoporosis, and act
by reducing and/or inhibiting bone resorption in the osteoporotic
patient. The following are examples in the art of bisphosphonates
currently being studied:
US Patent No. 4,621,077, issued Nov. 4, 1986 to Rosini
and Staibano discloses pharrnaceutical compositions comprising (4-
amino- 1 -hydroxybutylidene- 1,1 -bisphosphonic acid (ABP) or a
water-soluble (sodium, aniline or lysine) salt thereof.
Alendronate, 4-amino- 1 -hydroxybutylidene- 1,1 -
bisphosphonic acid monosodium trihydrate is a kno~vn bone
resorption inhibitor and is described in U.S. Patents 4,922,007 and
5,019,651 (Merck).
Clodronate, (dichloromethylene)bisphosphonic acid
di.sodium salt (Proctor and Gamble, is described in Belgium Patent
672,205 (1966) and its preparation is found in J. Org. Chem 32,
4111 (1967).
Tiludronate, ([(4-chlorophenyl)thiomethylene]-
bisphosphonic acid) (Sanofi) is described in U.S. Patent 4,g76,24
issued October 24, 1989.
YM 175 ([(cycloheptylamino)methylene]bisphosphonic
acid, disodium salt) by Yamanouchi is described in U.S. Patent
4,970,335 issued November 13, 1990.
CA 022234~0 1997-12-04
W O 96/39107 PCT~US96108515
- CGP 42'446, being 2-(imidazol-1-yl)-hydroxyethyl-
idene-1,1-bisphosphonic acid is a Ciba Geigy compound and is
described in Bone and Mineral, Abstracts, Supplement 1 to Vol 25,
April 1994, S61, Article 12, by A. Pataki et al.
Ibandronate, BM 21.0995 (1-Hydroxy-3-(methylpentyl-
aLmino)-propylidene-bisphosphonate) by Boehringer-M~nnheim - is
described in U.S. Patent 4,927,814 issued May 22, 1990.
A study by Proctor and Gamble (Norwich Eaton
Pharmaceuticals) using risedronate, whose chemical name is sodium
trihydrogen [1 -hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, in
combination with estrogen showed a positive effect of both of these
agents to prevent or reverse bone loss in ovariectomized rats
(published in Abstracts 731 and 732 at the Fall 1992 ASBMR
meeting in Minnesota).
The article, "J. Clin. Invest.", Jan. 1992, 89 (1), p. 74-
78 by J. Chow et al., describes a study on ovariectomized rats in
which bone resorption was suppressed by pamidronate whose
chemical name is 3-amino-1-hydroxy propylidene-bisphosphonic acid
disodium salt. They concluded that pamidronate inhibits bone
resorption.
Mildronate, a derivative of parnidronate, 3-(N,N-
dimethyl)arnino-l-hydroxy-propylidene-bisphosphonic acid,
dimethyl-APD, is described in Bone and Mineral, Abstracts,
Supplement 1 to Vol 25, April 1994, S79, Article 7~, by D. Gonzalez
e~ al.
Another Proctor and Gamble compound, piridronate.
[2-(2-pyridinyl)ethylidene]-bisphosphonic acid, monosodium salt is
described in USP 4,761,406 as having bone resorption inhibition
activity.
Quaternary nitrogen derivatives of piridronate,
including NE-5~051, NE-5~095, NE-5~043, NE-10244, NE-1-0446
are described in Bone and Mineral, Abstracts, Supplement 1 to Vol
25, April 1994, S65, Article 24, by F. H.Ebetino et al.
CA 022234~0 1997-12-04
W O 96/39107 PCTAJS96/08515
The article, "Monatschefte" 99, 2016 (1968) by
F. Kasparet describes the synthesis of etidronate~ hydroxy-
ethylidene)bisphosphonic acid, disodium salt, (Proctor and Gamble).
The above bisphosphonates are readily water soluble.
5 For extended bioavailability in the area of the periprosthetic bone,
water-insoluble bisphosphonate salts, e.g., calcium salts, would also
be desired for formulating a cement.
US Patent No. 4,446,052, issued May 1, 1984 to
Sunberg and Benedict, discloses a gel comprising di[(3-amino-1-
10 hydroxy-propylidene)-l,l-bisphosphonic acid]tricalcium salt in
water. The gel is disclosed to be useful for the treatment of certain
disorders of calcium metabolism in warm blooded ~nim~ls.
US Patent 5,356,887, issued October 18, 1994 to
Brenner et al. and assigned to Merck & Co., Inc., discloses three new
15 insoluble calcium salts of alendronate: [(4-amino-1-hydroxy-
butylidene)-l,l-bisphosphonic acid]monocalcium salt, (ABP)Ca;
di [(4-amino- 1 -hydroxybutylidene)- 1,1 -bisphosphonic acid]mono-
calcium salt, (ABP)2Ca; and tri[(4-amino-1-hydroxybutylidene)-1,1-
bisphosphonic acid]tetracalcium salt, (ABP)3Ca4. These salts are
20 described as useful in intramuscular or subcutaneous injection.
However, the above cited art does not suggest or
describe the use of a bisphosphonate being incorporated into a
polymethyl-methacrylate bone implant cement to specifically prevent
aseptic loosening and bone resorption in the periprosthetic bone area
25 of an orthopedic implant device.
What i,s desired in the art is a bone implant cement to
optimally prevent excessive bone resorption in the periprosthetic
area of an implant device, i.e., the bone area which is in contact and
close proximity to the cement surface, to retard the aseptic loosening
30 and failure of the device and thereby to prevent the pain, morbidity
and cost associated with this condition.
CA 022234~0 1997-12-04
W O ~6/39107 PC~AUS96/08515
~UMMARY OF THE INVENrrION
We have discovered that a bisphosphonate salt can be
used in a bone fixation cement for patients for the prevention of
i~ailure of joint prostheses, e.g., for the hip or knee. A~lmini.stration
S of a fixation cement cont~inin~ a bisphosphonate, e.g., alendronate,
can provide extended therapeutic action and prevent the
periprosthetic bone resorption process and thereby m~int~in the
integrity of the total prosthetic structure.
By this invention there is provided a bone implant
cement comprising a pharmaceutically acceptable polymeric carrier
~nd an effective amount of a bisphosphonate bone resorption
inhibitor.
The bisphosphonate applicable in the cement includes the
free acids, and pharrnaceutically acceptable salts, e.g., sodium,
potassium, ammonium, calcium, magnesium and barium salts of:
alendronate, clodronate, tiludronate, YM 175, ibandronate (BM
21.0995), risedronate, piridronate, pamidronate, or combinations
tlhereof.
Further provided is a method of preventing failure of a
joint prosthesis implanted into a bone cavity in the presence of an
orthopedic bone cement in a patient comprising the steps of:
(a) adding a bisphosphonate to the orthopedic bone
cement;
(b) adding the cement from step (a) to the bone cavity;
(c) implanting the joint prosthesis into the bone cavity.
DETAILED DESCRIPTION OF THE ~VENTION ANI)
PREFERRED EMBODIMENTS
The bisphosphonates described above are useful in the
invention cement. Very useful are the sodium, potassium and
calcium salts of residronate, clodronate, tiludronate and alendronate
and particularly useful are the sodium and calcium salts of
alendronate, i.e., monosodium alendronate trihydrate, disodium
CA 022234~0 1997-12-04
W O 96/39107 PCT~US96/08515
alendronate, anhydrous monosodium alendronate, di[(3-amino-1-
hydroxypropylidene)- l, l -bisphosphonic acid]tricalcium, [(4-amino-
l-hydroxybutylidene)-l,l-bisphosphonic acid]monocalcium salt,
(ABP)Ca, di[(4-amino- l -hydroxybutylidene)- l, l -bisphosphonic
S acid]monocalcium salt, (ABP)2Ca, and tri[(4-amino-l-hydroxy-
butylidene)-l,l-bisphosphonic acid]tetracalcium salt, (ABP)3Ca4.
The cement disclosed herein can be used to treat human
subjects at the time of insertion of a prosthesis, i.e., a medical
implant device.
The method described herein involves the ~lministration
of a bisphosphonate fixation cement in an osteogenically effective
amount to inhibit bone resorption in the periprosthetic bone area of a
medical implant device.
By the term "periprosthetic bone area" as used herein is
meant the area of bone which is in contact with the medical implant
device, including the cement, or in the immediate proximity thereof.
By the terrn "sodium alendronate" as used herein, is
meant alendronate, being 4-amino- l -hydroxybutylidene- l, l -
bisphosphonic acid monosodium trihydrate.
By the term "calcium alendronate" as used herein, is
meant the above four listed insoluble calcium salts.
Very useful bisphosphonate,s salt in the invention are
alendronate and calcium alendronate.
By the term "insoluble" as used herein, is meant that the
aqueous solubility of the bisphosphonate, calcium alendronate, at
room temperature is not appreciable.
The term "inhibition of bone resorption" as used herein
refers to prevention of bone loss, especially the inhibition of removal
of existing bone either from the mineral phase and/or the organic
matrix phase, through direct or indirect alteration of osteoclast
formation or activity. Thus, the term "inhibitor of bone resorption"
as used herein refers to agents that prevent bone loss by the direct or
indirect alteration of osteoclast formation or activity.
CA 022234~0 1997-12-04
W O 96/39107 PCTrUS96/08515
The term "osteogenically effective" as used herein means
that amount which decreases the turnover of mature bone. As used
herein, an osteogenically effective dose is also "pharmaceutically
effective."
The t~rm "subject" as used herein refers to a living
vertebrate ~nim~1 such as a m~mm~l in need of treatment, i.e., in
need of an implant device
The term "preventing" as used herein shall mean
providing a subject with an amount of a bisphosphonate in a bone
cement sufficient to act prophylactically on the bone cavity and the
periprosthetic bone area to prevent the loosening of the implant
device.
By the term "cement", as used herein, is meant to
encompass the mixed cement composition cont~inin~ all of the
ingredients and components prior to, during, and after complete
"curing", i.e., during early stages of monomer polymerization, at
partial polymerization and complete polymerization. Thus, the term
"cement" can include the kneaded precured mass cont~ining
unpolymerized methylmethacrylate just prior to insertion into the
bone cavity, the inserted mass just after insertion, and the fully
polymerized cement, i.e., "fully cured", inside the bone cavity in
contact with the prosthetic bone and the implant device after
sufficient time for complete curing, e.g., 15-20 minutes.
In general, conventional bone cements currently used in
arthroplastic procedures are FDA approved "cold" self-curing
polymethylmethacrylate (PMMA)-based compositions which cure at
room temperature or body temperature.
Generally bone cements have to be prepared
immediately prior to using and and consist of two parts: first, a solid
acrylate polymer part, which is generally a sterile package cont~ining
fully polymerized polymer, e.g., PMMA beads of subst~nti~lly
uniform small particle size of about 5-20 microns average diameter,
and a catalyst, e.g., a solid aromatic peroxide such as benzoyl
peroxide, present in about in one weight percent or less; and a second
CA 022234~0 1997-12-04
W O 96/39107 PCTrUS96/08515
part, containing the acrylate monomer, which is generally a sterilized
ampoule cont~ining the acrylate or methacrylate monomer, e.g.,
methylmethacrylate, and an initiator, e.g., an N,N-disubstituted
aromatic amine such as N,N-dimethyl-p-toluidine, present in about
S one weight percent or less. The second part can also contain a small
quantity of a monomer stabilizer e.g., hydroquinone or a
dicarboxylic acid, such as ascorbic acid in about 0.02 weight percent
or less of the composition. A small amount of ethyl alcohol in about
one weight percent or less can also be present to help solubilize the
10 ascorbic acid. When the initiator comes into contact with the catalyst
upon mixing of the polymer powder and monomer parts, the
activator-catalyst interaction activates the catalyst to initiate the
polymerization of the monomer.
The polymer powder part can also contain a
15 radiopaquing agent, e.g., zirconium oxide or barium sulfate, present
in about 5-15 weight percent of the composition, to distinguish the
cement from bone during subsequent X-ray analysis and monitoring
of the implanted device.
Both the polymer powder and monomer parts can also
20 contain a non-toxic pigmented coloring agent e.g., chlorophyll,
present in less than 0.1 weight percent, to enable easy identification
in the surgical room during handling and preparation.
Further, an antibiotic can be included in the polymer
powder part, e.g., gentamicin sulfate, or tetracycline, present in
25 about 1-2 weight percent or less, to prevent bacterial infection in the
periprosthetic area.
The separately packaged polymer powder can be
sterilized prior to use with, e.g., gamma radiation; the monomer can
be sterilized by e.g., sterile microfiltration; and the package
30 containing the polymer part can be sterilized by e.g., ethylene oxide.
In practice, the contents of the polymer powder and
monomer parts are mixed in an area having an exhaust system in the
surgical room just prior to application. All sterile instruments are
used in the mixing procedure. The monomer is added to the
-
CA 022234~0 1997-12-04
W O 96139107 PCT~US96/08515
polymer powder during mixing at room temperature being careful
not to entrap air and create air voids. Care must be taken in
handling the monomer since it is volatile and fl~mm~kle. The
polymerization of the monomer begins which binds together the
polymer producing a dough-like mass over a 1-2 minllte period. The
mass is kneaded to a desirable consistency and then placed into the
bone cavity, which has been previously washed with cold saline
soution and dried, under a slight pressure, by sterile gloved hand,
sterile spatula, or by a syringe applicator to force the cement into the
spongy areas of the bone to elimin~te "air pockets" between the bone
cavity and ~e cement. The reason for this is that the cement is not
an adhesive and depends upon mechanical interlock of bone, cement
and implant surfaces for good fixation. The implant device is then
firmly inserted into the bone cavity and the excess cement removed.
The implant is held firmly in place until complete curing occurs in
about a 7-8 minute period. The rest of the arthroplastic structure is
then assembled.
The cement useful herein contains a bisphosphonate
admixed with a polymeric base.
Representative examples of polymers that can be used as
the polymeric base for fixation of bone implants are polyacrylic acid
ester and polymethylacrylic acid ester types, e.g., polymethacrylate
and polymethylmethacrylate, including copolymers of polyacrylic
acid ester/polymethacrylic acid ester, and copolymers with polyaLkyl-
methylmethacrylate. Specific polymers include:
polyalkylmethacrylates including polymethylmethacrylate (PMMA)
and polyethylmethacrylate, polymethacrylate, polymethylmeth-
acrylate/polymethacrylate copolymers, copolymers of methyl-
methacrylate including methylmethacrylate/n-decylmeth-
acrylate/isobornylmethacrylate, copolymers and mixtures thereof the
above polymers, and the like. A very useful polymer is
polymethylmethacrylate.
CA 022234~0 1997-12-04
W O 96~9107 PCTrUS96/0851
- 10 -
The dosage or amount of bisphosphonate in the cement
necessary to achieve therapeutic effectiveness, will vary with the age,
size, sex and condition of the subject, the nature and severity of the
disorder to be treated, and the like; thus, a precise effective arnount
5 is best determined by the caregiver. In general terms, an effective
amount of biphosphonate is about 0.005 to 10 weight percent of the
total cement composition and a particularly useful range is 0.1 to 2
weight percent.
The method of the invention is useful for preventing
10 defects and disorders in the periprosthetic area of the joint prosthesis
which can result in a weakened or loosened structure and/or pain.
The bisphosphonate-cont~ining cement may be implanted
directly at the site to be treated, for example, by injection or surgical
implantation.
Bisphosphonate delivered in cement is useful for
m~int~ining implant fixation, by preventing or delaying the onset of
aseptic loosening.
Preparations of the bisphosphonates, disodium
alendronate and anhydrous monosodium alendronate, which are
20 operable in the cement, are shown below.
SUPPORTING EXAMPLE I
4-Amino- 1 -Hydroxy-Butylidene- 1,1 -Bisphosphonic Acid Disodium Salt
25 Monohydrate
To a suspension of 4-arnino-1-hydroxy-1,1-diphosphonic
acid (3.97 g) in 150 ml of distilled water was added with stirring
aqueous sodium hydroxide (0.5N) until the pH of the soution was 9.2.
The stirred solution was triturated with 200 ml ethanol (absolute) to
30 give a suspension of a fine white solid which was chilled at 5 degrees C.
overnight. The obtained solid was collected by vacuum filtration, air
dried, and then dried in vacuo at 100 degrees C. at 0.2 torr for 1~ hours
over P20~ to yield 4.38 g, (88%) yield of the disodium salt
CA 02223450 1997-12-04
W O ~6/39107 PCT~US96/08515
rnonohydrate title compound. A sample was submitted for CHN
analysis;
For C4Hl lNo4p2Na2:H2o:
Anal.: C, 15.44; H, 4.21; N, 4.50
Found: C, 15.28; H, 4.49; N, 4.49
Melting Point of the solid was above 300 degrees C.
Solubility of the disodium salt in water is about 200mg/ml
as compared to the free acid which is 8 mg/ml.
The solution pH of the disodium salt at 50 mg/ml. is 8.7, as
compared to the free acid which is pH 2.2 at ~ mg/ml.
SUPPORT~G EXAMPLE II
Interconver.sion of Hydrated Forms of Disodium Salt
The above obtained monohydrate from Example 1 is
exposed to a relative humidity atmosphere at 76% at room temperature
for 24-48 hours resulting in the pentahydrate salt.
Exposure of this pentahydrate salt to 0~o relative hurnidity
at room temperature for 24-48 hours results in a trihydrate salt.
The trihydrate salt is heated to 100 degrees C. for 1-4
hours and results in a 2.5 hydrate (hemipentahydrate) salt.
The hemipentahydrate salt can be heated between 100-150
degrees C. for 1-4 hours to produce the hemihydrate.
The hemihydrate salt can be heated from 150-250 degrees
C. for 1-4 hours to produce the anhydrous salt.
All of the above crystalline forms can be distinguished by
their water content.
CA 022234~0 1997-12-04
W O 96~9107 PCTrUS96/08515
- 12 -
SUPPORTING EXAMPLE m
Preparation of 4-Amino- 1 -Hydroxy-Butylidene- 1,1 -Bisphosphonic Acid
Monosodium Salt Anhydrate
S To a suspension of 4-amino-1 -hydroxy-l, l-diphosphonic
acid (4.02 g) in 150 ml of distilled water was added with stirring
aqueous sodium hydroxide (0.5N) until the pH of the soution was 4.40.
The stirred solution was triturated with 200 ml ethanol (absolute) to
give a suspension of a fine white solid which was chilled at 5 degrees C.
overnight. The obtained solid was collected by vacuum filtration, air
dried, and then dried in vacuo at 100 degrees C. at 0.2 torr for 18 hours
over P2O5 to yield 3.38 g, (91%) yield of the titled compound. A
sample was submitted for CHN analysis;
For C4H12NO7P2Na:
Anal.: C, 17.72; H, 4.46; N, 5.16
Found: C, 17.56; H, 4.67; N, 5.15
Melting Point of the solid was 244-245 degrees C.(d.)
The obtained titled salt displays a unique X-ray diffraction
pattern.
Solubility of the anhydrous monosodium salt in water is
about 300 mg/ml as compared to the free acid which is ~ mg/ml.
However, above 40mg/ml, the trihydrate precipitates out of the aqueous
solution.
The solution pH of the monosodium salt at 40 mg/ml. is
4.4, as compared to the free acid which is pH 2.2 at 8 mg/ml.
The water adsorption by the anhydrous salt at lower
humidities is quite slow.
The following Examples are given to illustrate the
carrying out of the invention as contemplated by the inventors and
should not be construed as being limitation.s on the scope and spirit of
the invention.
CA 02223450 1997-12-04
W O g6/39107 PCTAJS96/08515
- 13 -
EXAMPLE 1
The following are examples of PalacosTMR with
Gentamicin base cement, commercially available, including new
5 formulations with bisphosphonates, e.g., alendronate and calcium
alendronate. Palacos is a registered trademark of Heraeus Kulzer
GmbH Wehrheim, Germany, under license to Schering Plough,
Suffolk, England.
Part A (Polymer Powder)~0
Sterilized polymer packet Cont~inin~:
Ingredient Grams
Methyl methacrylate - methyl acrylate copolymer 33.80
Benzoyl peroxide 0.20
Zirconium dioxide 6.00
Chlorophyll 0.001
Gentamicin Sulfate 0.5
20 Part B (Monomer~
Sterilized ampoule (20ml) cont~ining:
In~redient Grams
Methyl methacrylate (stabilized with hydroquinone) 18.40
N,N-Dimethyl-p-toluidine 0.40
Chlorophyll 0.0004
Part B is added to Part A under sterile conditions with
30 simple mixing and 1.186 grams (2 weight percent based on the
weight of the cement composition prior to adding the
bisphosphonate) of 4-amino- 1 -hydroxybutylidene- 1, I -bisphosphonic
acid monosodiurn trihydrate (alendronate) is added during the
mixing step to achieve a uniform cement mixture cont~ining:
=
CA 022234~0 l997-l2-04
W O 96/39107 PCTrUS96/08515
- 14 -
Ingredient Grams
Methyl methacrylate - methyl acrylate copolymer 52.2
Alendronate 1. 186
Benzoyl peroxide 0.20
Zirconium dioxide 6.00
Chlorophyll 0.0014
Gentamicin Sulfate 0.5
N.N-Dimethyl-p-toluidine 0.40
Total 59-3
Similarly, 1.186 grams of a bisphosphonate selected from
clodronate, tiludronate, YM 175, ibandronate, etidronate, risedronate,
piridronate, pamidronate, 4-amino-1-hydroxybutylidene-1,1-
bisphosphonic acid monocalcium salt [(4-amino-1-hydroxybutylidene)-
15 l,l-bisphosphonic acid]monocalcium salt, (ABP)Ca; di[(4-amino-1-
hydroxybutylidene)-l,l-bisphosphonic acid]monocalcium salt,
(ABP)2Ca; and tri[(4-amino-1-hydroxybutylidene)-1,1-bisphosphonic
acid]tetracalcium salt, (ABP)3Ca4, or mixture thereof being 2 weight
percent of the cement composition, can also be used to produce separate
20 cement formulations.
Further, different amounts of bisphosphonate can be used,
for example, to achieve 0.005 to 10 weight percentages of the bone
resorption inhibitor in the cement composition.
EXAMPLE 2
1. Alendronate Effects on Bone Formation and Resorbability
of Bone Formed Durin~ Alendronate Treatment
Bisphosphonate drugs which prevent bone loss and/or
30 add back lost bone can be evaluated in the ovariectomized rat. This
~nim~l model is well established in the art (see, for example,
Wronski, ef al., (1985) "Calcif. Tissue Int." 37:324-328; Kimmel, et
al., (1990) "Calcif. Tissue Int." 46:101-1 10; and Durbridge, et al.,
(1990) "Calcif. Tissue Int." 47:383-387; these references are hereby
CA 022234~0 1997-12-04
W O 96~9~07 PCTrUS96/08~15
incorporated in their entirety). WIonski, et al., ((1985) "Calcif.
Tissue Int." 43:179-183)) describe the association of bone loss and
,, bone turnover in the ovariectomized rat. The bisphosphonate salts
applicable in the instant invention are active in this assay.
s
2. Alendronate Effects on Osteolysis and Localized
Infl~mm~tion in a Bone Cement
Following rat tibial marrow aspiration, according to the
procedure described in J. Bone Min. Research, Vol. ~, No. 3, pp. 379-
10 388 (1993) by L.J. Suva etal., a quantity, 10-100 milligrams of
polymethyl-methaclylate (PMMA) particles of about 5-10 microns
~verage diameter, which can be derived from the grinding of a PMMA
lblock, are introduced into the rat tibial medullary cavity and the bone
sealed using conventional bone wax. This serves as the control.
The opposite side of the rat tibia is treated at about the same
time and in the same manner except that the PMMA contains up to about
2 percent by weight of alendronate, either as the calcium or sodium salt,
or other pharmaceutically acceptable salt. The alendronate salt is
incorporated into the PMMA by simple mixing prior to polymerization
20 until a uniform mixture is achieved.
After 4-~ weeks, the ~nim~l is sacrificed, and the tibiae are
examined histologically and compared.
It is seen that the tibial medullary cavity cont~ining PMMA
particles without alendronate is expanded. This is evidence of localized
25 infl~mm~tion and osteolysis.
By contrast, the tibia containing the alendronate exhibits no
substantial localized infl~mm~tion or osteolysis, but instead, exhibits
new bone formation in the region of the PMMA particles.
Therefore, the alendronate-containing PMMA prevents
30 PMMA particle induced osteolysis and localized infl~mm~tion.
This is consistent with the method of ~mini.~tering a
bisphosphonate-containing cement, e.g., alendronate, to a patient's
periprosthetic bone area to prevent bone resorption and aseptic
CA 02223450 1997-12-04
W O 96~9107 PCT~US96/08515
- 16 -
loosening at the site of the medical implant device. The slowing of the
rate of bone resorption, but not its complete inhibition, is predicted to
be associated with an improvement in the local bone balance in the
periprosthetic bone which will provide greater integrity to the overall
S bone and prosthesis structure.
