Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-10-28
1999-10-12
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514108, A61K 3166
Patent
active
059655470
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/IB 95/00288, filed Apr. 25, 1995.
Arthroplasty, especially of the hip joint, is now a common procedure for the treatment of patients with osteoarthritis, rheumatoid arthritis and osteoporotic fracture. Approximately 800 000 hip replacements are performed globally each year. This number is rising steadily, younger patients are being treated and patients are living much longer and they all expect to lead a mobile, independent life. Despite the indisputable success of this technique, often complications arise and may eventually require costly surgical revision (3 or 4 revisions being not uncommon for a single patient).
The most common complications are aseptic prosthesis loosening [see for example H. Malchau et al., Acta Orthop. Scand. 64 (1993) 497-506; R. D. Mulroy Jr. and W. H. Harris, J. Bone Joint Surg. (Br) 72-B (1990) 757-760; M. Winter et al., Clin. Orthop. Rel. Research 282 (1992) 73-80] and migration of the prosthesis through bone without overt loosening [see for example B. B. Wroblewski and P. D. Siney, Clin. Orthop. Rel. Research 285 (1992) 45-47; M. Winter et al., loc. cit] These complications result in considerable morbidity, such as pain and reduced mobility. They occur with both cemented and uncemented prostheses, regardless of design, material or coating.
Previous approaches to prevent these complications have concentrated on alterations to the design of the prosthesis and the selection of different materials for its construction [see for example H. Malchau et al., loc. cit.; R. D. Mulroy Jr. and W. H. Harris, loc. cit.; M. Winter et al., loc. cit.; B. B. Wroblewski and P. D. Siney, loc. cit.; J. Wilson-MacDonald et al., J. Bone Joint Surg. (Br) 72-B (1990) 423-430]. Apart from some preliminary research with non-steroidal anti-inflammatory drugs [A. Ohlin and U. H. Lemer, Bone and Mineral 20 (1993) 67-78; J. H. Herman et al., J. Rheumatol. 21 (1994) 338-343], a pharmacological approach to prevent or treat the complications of arthroplasty, especially hip arthroplasty, has not been successful.
Methanebisphosphonic acid derivatives, in particular bisphosphonate compounds (=bisphosphonates), are used clinically to inhibit excessive bone resorption in a variety of diseases such as tumour-induced osteolysis, Paget's disease and osteoporosis [H. Fleisch, Handbook of Expl. Pharmacol. 83 (1988) 441-465]. Radiolabelled bisphosphonates are also used diagnostically to identify sites of high bone turnover [B. D. Collier et al., J. Nucl. Med. 34 (1993) 2241-2246; I. Fogelman et al., J. Nucl. Med. 34 (1993) 2247-2252].
In the orthopaedic field in general, there is a strong prejudice against using bisphosphonates. Firstly, attempts to use the commercially available bisphosphonate etidronate in the prevention of heterotopic ossification - which is another complication after arthroplasty but is very different from prosthesis loosening and prosthesis migration--proved either ineffective, or even detrimental due to a rebound effect [see for example D. E. Garland, Clin. Orthop. Rel. Research 263 (1991) 13-29; B. J. Thomas and H. C. Amstutz, The Hip 1987, 59-69; B. J. Thomas, Orthop. Clin. North America 23 (1992) 347-358].
Furthermore, there is increasing evidence that some bisphosphonates may inhibit bone formation and mineralization. Kanis, for example, teaches in Lancet 1984, 27-33 that bisphosphonates, as inhibitors of bone resorption, may delay the repair of microfractures by reducing the rate of remodelling. As another example, Reid et al. in Lancet 1988, 143-146 found that bisphosphonate treatment, in this particular case done with disodium pamidronate, caused a reduction in bone formation and a very low rate of bone turnover which raised the possibility of impaired microfracture repair. Adamson et al. [Lancet 342 (1993) 1459-1460] reports that pamidronate may inhibit bone mineralization in Paget's disease.
Surprisingly, it has now been found that certain methanebisphosphonic acid derivatives are useful for the cost-effective prevention or treatment of these complications of joint repl
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Goodship Allen E.
Green Jonathan
Kenwright John
Criares Theodore J.
Ferraro Gregory D.
Novartis Corporation
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