Bisphosphonates: a review of their novel anti-inflammatory properties and potential for the treatment of rheumatoid arthritis.
Bisphosphonates (BP) are synthetic pyrophosphates with a stable P-C-P bond replacing the more labile P-O-P bond. This structural class has been used extensively for the treatment of bone diseases, such as osteoporosis and hypercalcemia due to the propensity of BP to bind mineralized tissues and prevent bone resorption. Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis, pannus tissue formation and erosion of bone and cartilage, which is a major, disabling, pathogenic feature poorly managed with existing disease modifying anti-rheumatic drugs (DMARDs). A few investigators have used BP in combination with anti-arthritic therapy to treat the bone erosion component of RA, reports of which are mainly anecdotal. We review data suggesting that BP possess novel anti-inflammatory properties which may also be of benefit for the treatment of the chronic inflammatory component of RA, thus modifying the subsequent destructive disease process by mechanisms unrelated to direct inhibition of bone resorption. The rationale for pursuing this therapeutic approach to demonstrate BP anti-inflammatory activity will be reviewed. The subsequent design and synthesis of new BP chemical entities and their altered pharmacokinetic properties will also be discussed.
Dunn
C J
CJ
Department of Pharmacology, Pharmacia and Upjohn, Henrietta St, Kalamazoo, MI 49001, USA. colin.j.dunn@am.pnu.com
Slatter
J G
JG
Nugent
R A
RA