CA2223450A1

CA2223450A1 - Bisphosphonate cement composition to prevent aseptic loosening of orthopedic implant devices

Info

Publication number: CA2223450A1
Application number: CA 2223450
Authority: CA
Inventors: Hamish Simpson; Nick Athanasou; Ashley J. Yates
Original assignee: Individual
Current assignee: Merck and Co Inc
Priority date: 1995-06-06
Filing date: 1996-06-03
Publication date: 1996-12-12
Also published as: AU5973496A; WO1996039107A1; EP0831756A1; JPH11511041A

Abstract

Disclosed is a bisphosphonate bone cement for preventing periprosthetic bone loss and aseptic loosening of a joint prosthesis in patients, which cement contains a bisphosphonate bone resorption inhibitor, e.g., sodium or calcium salt of alendronate, and a pharmaceutically acceptable polymeric carrier such as polymethylmethacrylate.

Description

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 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 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 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 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.

W O g6/39107 PCTAJS96/08515 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 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.

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 W O 96~9107 PCT~US96/08515 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.

Claims

WHAT IS CLAIMED IS:

1. A bone implant cement comprising a pharmaceutically acceptable polymeric carrier and an effective amount of a bisphosphonate bone resorption inhibitor.

2. The cement of Claim 1 wherein said bisphosphonate bone resorption inhibitor is selected from the group consisting of: sodium, potassium, calcium, magnesium and barium salts of alendronate, clodronate, tiludronate, YM 175, ibandronate, risedronate, piridronate, pamidronate, or mixtures thereof.

3. The cement of Claim 1 wherein said bisphosphonate bone resorption inhibitor is sodium alendronate.

4. The cement of Claim 1 wherein said bisphosphonate bone resorption inhibitor is calcium alendronate.

5. The cement of Claim 4 wherein said calcium alendronate is selected from the group consisting of: di[(3-amino-1-hydroxypropylidene)-1,1-bisphosphonic acid]tricalcium; [(4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid]monocalcium salt;
di [(4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid]monocalcium salt; and tri[(4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid]tetra-calcium salt.

6. The cement of Claim 5 wherein said calcium salt of alendronate is [(4-amino-1-hydroxybutylidene)-1,1-bisphosphonic acid]monocalcium salt.

7. The cement of Claim 1 wherein said polymeric carrier is a polymethacrylate, polymethylmethacrylate, copolymer thereof, or copolymer with polyalkylmethylmethacrylate.

8. The cement of Claim 7 wherein said polymeric carrier is selected from the group consisting of: polymethyl-methacrylate, polyethylmethacrylate, polymethylmethacrylate-polymethacrylate copolymer, polymethacrylate, copolymer of methylmethacrylate/n-decylmethacrylate/isobornylmethacrylate.

9. The cement of Claim 8 wherein said polymeric carrier is polymethylmethacrylate.

10. The cement of Claim 1 wherein said bisphosphonate salt is present in about 0.005 to 10 weight percent of the total cement composition.

11. The cement of Claim 1 wherein said bisphosphonate salt is present in about 0.1 to 2 weight percent of the total cement composition.

12. The cement of Claim 1 wherein said bone resorption inhibitor is a calcium salt of alendronate and said polymeric carrier is polymethylmethacrylate.

13. The cement of Claim 1 wherein said bone resorption inhibitor is alendronate and said polymeric carrier is polymethyl-methacrylate .

14. The cement of Claim 1 further containing methyl methacrylate monomer.

15. The cement of Claim 1 wherein said polymethyl-methacrylate is fully cured.

16. 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.