Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-05-31
2004-01-20
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S103000, C514S104000, C514S107000, C514S108000
Reexamination Certificate
active
06680307
ABSTRACT:
This Application is a 371 of PCT/EP99/09252 filed Nov. 29, 1999.
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.
Bones serve mainly as a support, and consequently bone is frequently regarded as a simple building material. However, bone is a complicated biomaterial adapted to a wide variety of requirements, stimuli and noxae to which it is exposed. Endoprostheses are available as substitutes for bones and joints. However endoprostheses, even when biomechanically highly refined, do not have an active effect on the environmental and load factors.
Throughout the world, about 1.5 million hip-joint endoprostheses are implanted per year, including about 120,000 in Germany. There is also a considerable number of other joint prostheses, e.g. knee-joint, ankle-joint and shoulder-joint endoprostheses. It is expected that the number of primary-implanted endoprostheses, particularly the number needing to be changed, will continue to increase. Meanwhile even relatively young patients are provided with endoprostheses. The life expectancy of man is progressively increasing, so that in some cases up to 3 or 4 changes of prostheses may be expected for individual patients during their life. Cement-free implants are increasingly used in order to preserve bone substance during the first operation and particularly during any required replacement operations and because of the assumed longer survival time of the prostheses. Younger patients needing an endoprosthesis will profit in particular from this kind of tissue-preserving treatment. Longer-lasting endoprostheses are also necessary in view of increased life expectancy and for economic reasons.
Special consideration must therefore be given to the processes and morphological changes occurring in the time after the operation until final stabilisation of the implant bed in the bone, and to knowledge about the primary and secondary stability, particularly of cement-free endoprostheses, since cement-free anchoring of implants has become the preferred method.
“Primary stability” of an implant is described as the situation directly after implantation of the prosthesis in the bone. The prosthesis, via 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 is not yet incorporated in the bone.
Secondary stability, particularly in the case of hip prostheses, is usually attained only a few months after the bone grows into the prosthesis surface (osseointegration). In addition therefore to qualitative stabilisation there is a quantitative component, ensuring long-term stability of the prosthesis.
The process from primary stability to secondary stability goes through various phases. The first phase after prosthesis implantation is characterised by partial death of bone. Immediately after the operation, most parts of the neighbouring bone are intact. The subsequent partial bone death occurs over a few millimetres in the immediate neighbourhood of the prosthesis interface (the contact surface between the prosthesis and the bone). Dilated vessels and infiltration of polymorphonucleic cells occurs quickly at the boundary between still-living bone and dead bone, followed by fibroblasts, osteoblasts and osteoclasts. Repair occurs during the next stage. The dead bone tissue is infiltrated by granulation tissue and connective tissue. Macrophages and giant cells are occasionally observed. Newly-formed bone is superposed on the dead bone.
The third phase can last up to 2 years, during which the prosthesis is stabilised. During this time the dead bone material disintegrates and is replaced by woven and lamellar bone. At the end of the reconstruction process a narrow seam of connective tissue is frequently left 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 cement-free anchoring, as opposed to the cemented method, according to existing knowledge is that secondary stabilisation 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 Scan 1997; 68 (2):161-166 discloses that the secondary stabilising of hip prostheses takes up to 9 months. The results of his study are explained by the fact that the ingrowth of human trabecula bone occurs at a speed of about 1 micrometer per day. The maximum attainable ingrowth of the prosthesis occurs not before 9 months after the operation, even if surface-treated prostheses are used. This agrees with the observation of Krüger et al. (Teilbelastng oder Vollbelastung—Therapiestrategie nach zementfreier Hüfttotalendoprothese Orthop Praxis 1998; 34 (5):287-293). In all cases Krüger noted additional sintering of the prosthesis shank during the first 6 months after the operation, with formation of a delicate sclerosis line in the Gruen zone 1. Also Wall et al. (Auswertung der Osseointegration von zementlosen Hüftprothesenstielen mit Computerauswertung digitaler Röntgendensitometrie Orthop. Praxis 34:73-77 1998) showed a decrease of 18% in the optical density of the bone tissue in all Gruen zones during the first 6 months after the operation, irrespective of which of the two types of prosthesis was investigated. Only thereafter was there a renewed increase of bone density, for 24 months after the operation only a starting value of 92 to 97% had been reached. In many centres, therefore, patients keep the operated leg stress-free for up to 6 months after the operation. This is to prevent the prosthesis 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) secondary integration of the bone into the prosthesis, disturbed by pathological micromovements (>150 micrometers) results in formation of connective tissue on the interface between the bone and prosthesis. This, and the resulting fear of fractures, make it necessary to relieve stress on the prosthesis for a prolonged period. This greatly slows the rehabilitation of patients, and may result in more and longer-lasting complaints.
On the other hand, a reduced mechanical load on the bone (stress shielding) results in periprosthetic bone atrophy, which may last up to a year and is regarded as a reason for premature loosening of the cement-free prosthesis.
The operations, the duration of post-operative after-treatment in clinics, the non-productive time during the rehabilitation phase, re-integration of younger patients in the work progress and subsequent operations result in enormous costs to the community.
The main proposals hitherto for improving the early and long-term results after endoprosthetic replacement are: improving the design of prostheses with proximal introduction of force, rotational stability, surface coatings and press fit of cement-free endoprostheses. In present clinical treatment there is no use of drugs for increasing the ingrowth of endoprostheses, although the use of growth factors (e.g. BMPs) in conjunction with cement-free implants has been studied in recent research (Proceedings of the annual meeting of the ORS 5, 245, 339, 599 1998 New Orleans).
On the other hand drugs from the amino-bisphosphonate group have a positive influence on “bone remodelling” and produce an increase in bone mas
Bauss Frieder
Kurth Andreas A.
Fay Zohreh
Johnston George W.
Kwon Brian-Yong
Lau Bernard
Rocha-Tramaloni Patricia S.
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