MXPA01005462A - Use of ibandronate for promoting osseointegration of endoprostheses - Google Patents

Abstract

The invention relates to use of ibandronic acid (1-hydroxy-3-(N-methyl-N-pentyl)aminopropyl-1, 1-diphosphonic acid) or physiologically compatible salts or esters thereof for improving the osseointegration of cement-free anchored endoprostheses. Ibandronate or salts thereof is applied for a short time immediately after insertion of an endoprosthesis, with the surprising result that secondary stability of the implant is obtained in only 5 weeks or less after the operation.

Description

USE OF IBANDRONATE TO PROMOTE OSEOINTEGRATION OF ENDOPROTESIS Background of the Invention. The invention relates to the use of ibandronic acid (1-hydroxy-3- (N-meth i 1-N-pentyl 1) to inopropyl 1- 1, 1-di-phosphonic acid) or physiologically compatible salts or esters thereof to improve bone integration of cement-free anchored endoprostheses. Ibandronate or salts thereof are applied for a short time, immediately after insertion of a stent, with the surprising result that secondary stability of the implant is obtained in only 5 weeks or less after the operation. The bones serve mainly as a support and consequently the bone is often considered as a simple structural material. However, bone is a complicated biomaterial adapted to a wide variety of requirements, stimuli and noxious to which it is exposed. Stents are available as replacements for bones and joints. However, stents, even when they are biomechanically very RED .: 129581 refined, do not have an active effect on the factors of the surrounding environment and load. Around the world, approximately 1.5 million hip joint stents are implanted per year, including approximately 120,000 in Germany. There is also a considerable number of other joint prostheses, for example, stenting of the knee joint, the ankle joint, and the shoulder joint. It is expected that the number of primary implanted stents, particularly the number that needs to be replaced, will continue to increase. Meanwhile, even relatively young patients have endoprotesis. The life expectancy of men increases progressively, so in some cases 3 or 4 prosthetic replacements are expected for individual patients throughout their lives. Cement-free implants are increasingly used to preserve the bone substance during the first operation and particularly during any desired replacement operation and due to the survival time of the prostheses, which is assumed to be longer. The most patients Young people who require an endoprosthesis will benefit particularly from this type of treatment that preserves tissues. Stents of longer duration are also necessary considering the higher life expectancy and economic reasons. Special consideration should therefore be given to the procedures and to the morphological changes occurring in the time after the operation until the final stabilization of the implant bed in the bone and to the knowledge with respect to the primary and secondary stability, particularly of cement-free stents, since the free anchorage | cement of the implants has become the preferred method. The "primary stability" of an implant is described as the situation directly after the implantation of the prosthesis in the bone. The prosthesis, by means of its distal part, is anchored either in the intramedullary canal in the diaphysis (cortical bone) or in the proximal metaphysis of the trochanter prominence. This primary stability is only qualitative, since the prosthesis has not yet been incorporated into bone. ^ s ^ ¡^^^ Secondary stability, particularly in the case of hip prostheses, is usually achieved only a few months after | the bone grows on the surface of the prosthesis (bone integration). In addition to qualitative stabilization, there is a qualitative component that ensures the long-term stability of the prosthesis. The process of primary stability to I secondary stability goes through several phases. The first phase after the implantation of the prosthesis is characterized by partial bone death. Immediately after the operation, most of the surrounding bone is intact. Subsequent partial bone death occurs in a few millimeters in the vicinity of the interface of the prosthesis (the contact surface between the prosthesis and the bone). Rapidly dilated vessels and infiltration of polymorphonuclear cells are observed at the boundary between the bone that is still alive and the dead bone, followed by fibroblasts, osteoblasts and osteoclasts. The repair occurs during the next stage, i The tissue of the dead bone is infiltrated by granulation tissue and connective tissue. They look themselves occasionally macrophages and giant cells. The newly formed bone overlaps the dead bone. The third phase can last up to two years, during which the prosthesis stabilizes. During this time the dead bone material disintegrates and is replaced by interwoven bone and laminlar. At the end of the reconstruction process i there is often a narrow seam of connective tissue between the bone and the smooth surface of the prosthesis. These phases are also influenced by the individual characteristics of the patient such as bone metabolism (osteoporotic, osteopenic, juvenile) and extrinsic factors such as relief of stress on the prosthesis after the operation and the form of rehabilitation. The disadvantages of the cement-free anchor, as opposed to the cemented method, according to the existing knowledge, is that I the secondary stabilization of a prosthesis occurs after a period of not less than 6-8 weeks. Hofmann et al., ("Progression of human bone ingrowth into porous-coated implants." Acta Orthop, Sean., 1997; 68 (2): 161-166, reveal that the secondary stabilization of the prosthesis of "-.-- * ... ----- .-- -..--. -. -.-zuaA ». -. ' * The hip requires 9 months. The results of this study are explained by the fact that inward growth of human trabecular bone occurs at a rate of approximately 1 micrometer per day. The maximum inward growth of the prosthesis that can be achieved occurs not earlier than 9 months after the operation, even when prostheses treated on the surface are used. This agrees with the observation of Krüger et al. ("Teilbelastungoder Vollbelastung - Therapiest rategie nach zementfreier Hüfttotalendoprothese." Orthop Praxis 1998; 34 (5): 287-293). In all cases Krüger additional sintering of the prosthesis stem was observed during the first 6 months after the operation with formation of a delicate sclerosis line in the area of Gruen 1. Also Wall et al. ("Auswertung der Osseointegration von zementlosen Hüftprothesenstielen mit Computeraus ertung digitaler Rontgendensitomet rie. "Orthop Praxis 34: 73-77, 1998) showed a decrease of 18% in the optical density of bone tissue in all areas of Gruen during the first 6 months after the operation, regardless of which of the Two types of prostheses were investigated. Only afterwards was there a renewed increase in bone density since 24 months after the operation solq a starting value of 92 to 97% was reached. In many centers, therefore, patients keep the operated leg free from stress until 6 months after the operation. This is to prevent the prosthesis from sinking further into the bone or causing fractures. According to Burke et al. ("Micromotion of cemented and uncemented femoral components." J.Bone Joint Surg. 73B: 33-38, 1991) the secondary integration of the bone in the prosthesis disturbed by pathological micromovement (> 5 micrometers). ) results in training | of connective tissue at the interface between the bone and the prosthesis. This, and the resulting means with respect to fractures, makes it necessary to relieve stress on the prosthesis for a prolonged period. This makes the rehabilitation of patients much slower and can result in more disorders and for a longer time. On the other hand, a reduced mechanical load on the bone (stress shield) results in periprosthetic bone atrophy, which may last lhtfM --------------- i --- *** - * • * - up to one year and is considered a reason for premature loosening of the cement-free denture. The operations, the duration of the post-operative treatment in the clinics, the time, non-productive during the rehabilitation phase, the reintegration of the youngest patients in the work and the subsequent operations result in enormous costs for the community. 10 The main proposals to improve the early and long term results after endoprosthetic replacement are: to improve the design of the prosthesis with proximal introduction of force, rotation stability, 15 surface coatings and snap-fit cement-free stents. In the current clinical treatment no drugs are used to increase the ingrowth of the endoprostheses although the use of growth factors (for example, BMP) together with cement-free implants has been studied in recent investigations (Proceedings of the Annual Meeting of the ORS 5, 245, 339, 599, 1998, New Orleans). On the other hand, the drugs of the inobisphosphonate group have a positive influence on --aá - ü- ^^ - ^^^^^^^^^^ ^^^^ 444 && "bone remodeling" and produce an increase in bone mass and bone quality, particularly in the investigation of osteoporosis. Pre-clinical knowledge of the biological and physical properties of bisphosphonates has been available for approximately 30 years. Each bisphosphonate has its own chemical, biological and physiological properties and consequently its own activity profile. Bisphosphonates can be used, among others, in bone surgery. For example, the use of bisphosphonates in bone surgery is known from the O 94/21266 A1. Clodronate in particular, is used before and / or after a transplant operation to increase the formation of bone tissue and / or to eliminate complications after implantation. A daily dose of 0 ^ 01-100 mg / kg, preferably 0.5-20 mg / kg for parenteral use, 0.5-5 mg / kg for intravenous application and 10-100 mg / kg for oral use is mentioned. It is recommended to start the treatment 1 to 3 weeks before the operation and / or to continue for preferably 1 to 6 months after Jna ^^^ g »t ^^ y? iMtíte?» »BÉjtó ^^^^^^ operation. In the case of bone transplantation, it was shown that after 35 days a new bone formation occurred in almost all the transplants in the treated animals. It was shown, with reference to a tooth implant in the explanted bone, that after treatment with Clodronate for 4 weeks (1 week before the operation and 3 weeks later), the osteogenesis (bone formation) is more intense than in the patients not treated with Clodronate. Bisphosphonates for the treatment and / or prevention of loosening and migration of stents are described in WO 94/30421 Al, WO 95/28936 Al and US 5,646,134. According to WO 95/30421 Al, it is recommended to prevent loosening and migration of the prostheses by administering a bisphosphonate before, during and after the operation. The proposed dose is between 0.002 and 3.40 mgfkg preferably 0.01 - 2.40 mg / kg, administered continuously, ie daily at cyclic intervals, the animals (sheep) that were used in the assay were treated with a bisphosphonate intravenously immediately after the operation. If required, the iUHMIÉ -------- .- ^ - ^ treatment should be continued at intervals, for example, every 4 or 8 weeks. The housing of the prosthesis was controlled monthly and after a year the additional controls showed that the compounds gave adequate protection with respect to the loosening of the prostheses. No detailed results were revealed. Nor is it established that substances were used. As the embodiments show forms I of administration of pamidronate, risedronate and EB 1053, it is assumed that these compounds are preferred. According to WO 95/28936 A1 and US Pat. No. 5,646,134, bisphosphonates, preferably alendronate, are used to prevent the loss of periprostatic bone by inhibiting bone resorption and to reduce the pain associated with bone loss. Alendronate is preferably administered orally or parenterally, or alternatively the orthopedic implant can be coated with | a bisphosphonate to increase the grip on the rubber during the operation. The effective dose | it is between 1.5 and 3000 μg / kg body weight, preferably 10 μg / kg. Bone resorption can not be stopped completely but it can be ß íM MÜ¡ÉI ¡--b -------- Mui --- É ---- á --- ------ a- -IÉrár- i í iiii ^ - ** & * considerably delayed by means of treatment with higher doses of alendronate. Description of the Invention The object of the invention is to improve the bone integration of the endoprostheses achieving a secondary stability as soon as possible and thus accelerating the rehabilitation of patients. It has been unexpectedly found that i the bone integration of endografts, particularly joint prostheses such as stents of the knee joint, the ankle joint or the shoulder joint, and in particular, preferably, the prostheses of | the joints of the hips, is accelerated and the secondary stabilization of | the prosthesis after only 5 weeks, preferably after 2 to 4 weeks, I by means of the short-term administration, directly after the operation, of ibandronic acid (l-hydroxy-3- (N-methyl-N- pentyl) aminopropyl-1,1,1-di phosphonic acid) or physiologically compatible salts or esters thereof. "Bone integration" means a connection functional and structural direct between the vital bone and the surface of the implants under load The administration of ibandronate in the short term, beginning during the operation, during a period of approximately 2-4 weeks and 1 to 7 times per week or at cyclic intervals (depending The individual characteristics of the patient such as age, sex and bone metabolism (osteoporotic, osteopenic, juvenile) prevents bone resorption caused by osteoclasts and, due to the predominance of the osteoblastic reaction, promotes an increase in bone growth in the The result is a rapid increase in bone mass around the prosthesis.The administration of ibandronate results in the formation of a greater amount of integrated bone, its earlier maturation and the prevention of osteopenia around the prosthesis. the duration of the reduced mechanical load on the patient's intact bones, particularly in the In case of operations of the hip joint, could be reduced considerably, the risk of bone loss was zero or insignificant. ^^ «^ £ * ^^ ^? ^^^^ s Sodium salt of ibandronic acid is preferably used. Ibandronic acid or pharmaceutically acceptable salts thereof, preferably the sodium salt, are well known in the art. Ibandronic acid or pharmaceutically acceptable salts thereof have been described, for example, in European Patent Application No. 252,504 and U.S. Patent No. 4,927,814. Ibandronic acid or pharmaceutically acceptable sajles thereof can be administered as liquids, solids, or orally in the form of an aerosol, or in an enteral, parenteral, topical, nasal, pulmonary or rectal form in all excipients, adjuvants and pharmaceutically accepted, non-toxic, conventional additives. The term "parenteral" includes subcutaneous, intravenous and intramuscular administration or infusions. The oral administration forms can be, for example, tablets, capsules, dragees, syrups, solutions, suspensions, emulsions, elixirs, etc., which may contain one or more additives between the following groups, for example, flavorings, Sweeteners, colorants and preservatives. The oral administration forms contain the active component together with pharmaceutically acceptable, non-toxic excipients suitable for producing tablets, capsules, dragees, etc., such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), peanut oil, oli oil, va, paraffin, migliol, gelatin, agar, stearate | of magnesium, beeswax, cetyl alcohol, lecithin, glycerol, animal or vegetable fats or high molecular weight solid polymers such as polyethylene glycols. The tablets, capsules, dragees, etc., can receive a suitable coating, for example, | of glyceryl monostearate or glyceryl distearate to avoid side effects in the stomach, or to delay absorption in the gastrointestinal tract i and thus prolong the period of action. Preferred means for injections are sterile injectable aqueous or oily solutions or ----- MMÉI-i ^^^^ m suspensions containing the usual additives as stabilizers and solubilizers, if required. Examples of such additives are, for example, isotonic common salt solution, 1, 3-but anodiol, 5 fatty acids, such as oleic acid, monodiglycerides, diglycerides or miglyol. For rectal use, all suitable non-irritating additives, which are solids at abnormal temperatures and liquids at rectal temperature, can be used. example, cocoa butter or polyethylene glycol. The usual pharmaceutical excipients can be applied in the form of an aerosol. Creams, tinctures, gels, solutions or suspensions, etlc., With usual pharmaceutical additives are used externally. Accordingly, the present invention comprises the use of ibandronic acid or physiologically compatible salts or esters thereof to improve bone integration of cement-free anchored stents or stent by short-term administration directly after the operation and in the range of two to four weeks The intravenous equivalent daily dose i of ibandronate is preferably 0.1 μg / kg to 100 μg / kg body weight, preferably 1 to 100 μg. μg / kg of body weight. A daily dose of 20 to 30 μg / kg body weight is particularly preferred, and results in complete integration after only 15-20 days. When used in accordance with the invention, the ibendronate is preferably found | in the form of a solution for parenteral administration, containing the active substance I in a proportion of 0.01-20 mg. When other administration forms are used, the dose has to be adjusted according to the bioavailability of the administration form. The present invention therefore relates particularly to the use of ibandronic acid or its physiologically compatible salts, preferably the sodium salt, or esters, to improve the bone integration of cement-free anchored stents by means of post-operative direct administration. in the short term within a period of two to four weeks. Ibandronate may be used in a dose I of 0.1 to 100 μg / kg of body weight, preferably 1 to 100 μg / kg of body weight, ibandronate may also be administered as a solution for parenteral use with an active substance content.

• MMM- - * - »- * • - **" -'-- fc'a- * »*** ~ - ^" -,, ^ AaBh from 0.01 to 20 mg. The application can be performed one to seven times a week. The use of ibandronic acid, as described, can also be performed by intermittent cyclic administration. The aforementioned uses are characterized by improving the bone integration of the hip joint endoprosthesis! The invention further relates to the use of ibandronic acid or its compatible physiological salts, or esters, to establish a secondary stability of the hip joint endoprosthesis within a period of 5 weeks after the operation. The use is characterized in that secondary stability is achieved after two to four weeks. The invention will now be explained in more detail with reference to the illustrated modes. EXAMPLES Material and method Female Spregue-Dawley rats were held for 6 months in cages and subjected to a 12 hour day and night rhythm. They had free access to food and water. The animals were kept and fed in accordance with legal regulations and The investigation was carried out with the approval under the supervision of the Gob presidency. Erno of Darmstadt. The animals were randomly divided among the various test groups. They were anesthetized by intraperitonal administration of cetaminaj (75 mg / kg) and xylazine (5 mg / kg). The hind legs were shaved and disinfected with betaisadonna solution. A midpararotulian arthrotomy of the knee joint was performed under aseptic conditions and the patella was laterally dislocated. The medullary canal was opened distally in the interdiffilar incision and the cjanal was drilled with a Kirchner wire 1.0 mm in diameter down to the proximal metaphysis of the femur. Then a titanium Kirchner wire was inserted into the right femur and a Kirchner wire coated with hydroxyapatite in the left femur to the proximal metaphysis. The access hole was closed with bone wax, the patella was replaced, the extensor apparatus of the refined leg was reconstructed, it was adapted to the soft tissue and the skin was closed by means of an intracutaneous seam. Then the hind legs were tested with respect to normal post-movement 3áéfc ^^^^^^^ g? É ^^^^^^ s ^^^^ * 3 ^^^^^^^^^^ operative. The animals could move freely in their cages and the activity and the load of the hind legs were controlled daily. Ibandronate or 0.9% NaCl was administered daily according to examples 1 and 2. After the predetermined treatment time the animals were sacrificed in a carbon dioxide chamber and then the two femurs were removed, they were completely released from the tissue and fixed in alcohol for the subsequent histological treatment. The complete rat femurs were visualized by X-rays in a lateral comparison to evaluate the macromolar phylogery and for documentation. Particular attention was paid to areas where a change in bone occurred, such as an increase or decrease in trabecular bone, a change in bone density, seams that loosened in the implant, periosteal or periosteal changes. The evaluation in this case was purely descriptive Description of the production of the preparations by the microsection cutting technique to produce histological sections of conventional tissue, which can not be cut, NM ----- I ----------- M according to Prof. Donath (K. Donath, G. Breuner:, A method for the study of undecalci f ied bones and teeth with attached soft tissue The Saege-Schli ff (sawing and grinding) technique. "J. Oral Pathology 1982, 11: 318-26.) The microsection cutting technique is a well-proven method for preparing thin sections smaller than 10 μm of conventional tissue. that can not be cut and materials (eg, long bones bearing implants) for histological diagnosis Histology Histological investigation of bones under the light microscope provides insight into the general structure and distribution of bone components. He made the histological fixation and the production of my crosections by the exact and ground cutting system of the firm Exakt-Apparat ebau (Norderstedt / Germany), coloring with toluidine blue.The coloring procedure is easy to carry out and the change in color gives information about d bone growth and reconstruction. Other coloring methods such as haematoxylin-eosin staining, van Giesoni staining or Masson-Golner staining, give good results. ? i | BÉiiiiijÉSi | ttiMi ?? representations of the impregnated fabric. The resulting preparations were then documented by photographs. The quantitative evaluation of the results was done by hi s tomor fome t r -J a. Hi s tomor fo etri a The area covered with bone in the metal implant was shown and calculated by its parent fome trí a, using special software. Example 1 la) Chronological sequence of the bone integration of titanium implants and hydroxyapatite-coated implants in the bone of Spregue-Dawley rats for months. Ib) Chronological sequence of the bone integration of titanium implants and hydroxyapatite-coated implants in the bone of Spregue-Dawley rats for 6 months after administration of 1 μg of AED / kg / d, 5 μg of AED / kg / d and 25 μg of AED / Kg / d of ibandronate (AED = free acid equivalent, that is, all doses refer to it). Four experimental groups were formed and the animals were randomly distributed among them. At each time, 2 animals of each group were operated and sacrificed. 1) Control group: Daily subcutaneous administration of 0.9% NaCl after implantation of the implants 2) experimental group 1: Subcutaneous administration (1 μq of AED / kg / d) daily of 1 μg of AED / kg / d of ibandronate after implantation of the implants. 3) Experimental group 2: Daily subcutaneous administration (5 μq of AED / kg / d) of 5 μg of AED / kg / d of ibandronate after implantation of the implants 4) experimental group 3: Daily subcutaneous administration (25 μq of AED / kq / d) of 25 μg of AED / kg / d of ibandronate after implantation of the implants The animals were sacrificed on 11 defined dates (days after implantation) as follows: 0, 4, 7, 10, 14, 18, 22, 27, 32, 37, 42. The other procedure was performed according to the description of the experiments. Evaluation The bone integration of the group treated with ibandronate was appreciably better compared to the untreated group. Near-complete inward growth occurred after 37 days in the untreated group while in the group treated with 25 μg of AED / kg / d of ubandronate, a complete integration occurred surprisingly after only 18 days, i.e. temporary advantage of more than 50% after treatment with ibandronate. Use 2 2a) Significant differences between the bone integration of titanium implants and the hydroxy apatiteo-coated implants in rat bones from 6 months to a defined time after the administration of 1 μg of AED / kg / d, 5 μg of AED / Kg / d and 25 μg of AED / Kg / d of ibandronate compared to an untreated control group. 2b) Significant differences between the bone integration of the titanium implants and the hydroxy apatiteo-coated implants in the rat bone of 6 months at a defined time from the administration of an ibandronate bolus at a total dose of 1 μg of AED / Kg / d, 5 μg of AED / Kg / d and 25 μg of AED / Kg / d of ibandronate once per d fgKHtfagHÍ t _-. -.--- H-ti ---,. .-----------, --- ^ ÉtiUMiJk day, compared to a control group not treated. 2c) Significant differences between the bone integration of the titanium implants and the implants coated with hydroxyapatite in the bone of rats of 6 months at a definite time between the administration of a bolus and a cumulative administration throughout the period. Seven experimental groups were formed and evaluated after 15-20 days, preferably after 18 days. The defined date was obtained from Example 1 (using a statistically sufficient number of 15 experimental animals, showing a significant difference between the groups (p < 0.01)). 1) Control group: Subcutaneous administration of 0.9% NaCl for 15-20 days after the operation. 2) Experimental group: Subcutaneous administration of 1 μg of AED / Kg / d of ibandronate for 15-20 days after the operation. - - • * ».-.-- ------- i. *. ^ A £ k) Experimental group: Subcutaneous administration of 5 μg of AED / Kg / d of ibandronate for 1 5-20 days after the operation. ) Experimental group Subcutaneous administration of 25 μg of FAE / Kg / d of ibandronate for 1 5-20 days after the operation. ) Experimental group Subcutaneous administration of a bolus of 1 μg of AED / kg / d of ibandronate for 1 5-20 days after the operation. ) Experimental group: Subcutaneous administration of a bolus of 5 μg of AED /: g / d of ibandronate for 15-20 days after the operation. ) Experimental group Subcutaneous administration of a bolus of 25 μg of FAE / Kg / d of ibandronate for 15-20 days after the operation.

Evaluation 2a) Very significant differences between the treated groups and the control group (50% increase after administration of 25 μg of AED / Kg / d of ibandronate compared to the contol group). 2b) Very significant differences between the groups treated with the bolus and the control group (50% increase after the administration of 25 μg of AED / Kg / d of ibandronate compared to the control group). 2c) No differences were found between bolus administration and cumulative administration. Consequently, the administration in a single bolus has appreciable clinical advantages. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. invention

Claims (16)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. 1. The use of ibandronic acid or physiologically compatible salts or esters thereof to improve bone integration of anchored, cement-free stents, by means of short-term administration directly after the operation and for a period of two to four weeks .
2. 2. The use according to claim 1, characterized in that ibandronate is administered at a dose of 0.1 to 100 μg / kg of body weight, preferably 1 to 100 μg / kg of body weight.
3. 3. The use according to claim 1 or 2, characterized in that ibandronate is administered in the form of a solution for parenteral administration with an active substance content of 0.01 to 20 mg.
4. 4. Use in accordance with the
5. 5. The use according to claims 1 to 3, characterized in that the administration is cyclic and intermittent.
6. 6. The use according to claims 1 to 5, characterized in that the bone integration of the stents of the hip joint is improved.
7. 7. The use of ibandronic acid and physiologically compatible salts or esters thereof to obtain the secondary stability of the hip joint endoprostheses in 5 weeks or less after the operation.
8. 8. The use according to claim 7, characterized in that secondary stability is achieved after 2 to 4 weeks.
9. 9. The use of ibandronic acid or physiologically compatible salts or esters thereof for the manufacture of drugs to improve the bone integration of anchored, cement-free stents, by means of short-term administration directly after the operation and within two to four weeks.
10. 10. The use according to claim 9, characterized in that the --- - - _2 ^^^ gg ^^^^^^ j ^^^^^ -_ ibandronate is applied at a dose of 0.1 to 100 μg / kg of body weight, preferably 1 ha sta 100 μg / kg of body weight.
11. The use according to claim 9 or 10, characterized in that ibandronate in the form of a solution is applied by parenteral application with an active substance content of 0.01 to 20 mg.
12. 12. The use according to claims 9 to 11, characterized in that the application is made from 1 to 7 times per week.
13. 13. The use according to claims 9 to 12, characterized in that the application is cyclical and intermittent.
14. 14. The use according to claims 9 to 13, characterized in that the bone integration of the stents of the hip joint is improved.
15. 15. The use of ibandronic acid and physiologically compatible salts or esters of the same for the manufacture of a medicament to obtain the secondary stability of the hip joint endoprostheses.
16. 16. Use according to claim 15, characterized in that secondary stability is achieved after 2 weeks.