BISPHOSPHONATES-CELLULAR MODE OF ACTION - INFLUENCE ON MEDIATORS WITHIN THE IMMUNE-SYSTEM

Bisphosphonates have been synthesised during the past 30 years in anal ogy to pyrophosphate. Inhibiting bone destruction diseases causing an osteoclastic bone resorption, bisphosphonates gain increasing importan ce in the treatment of osteolytic lesions in tumor patients. The basic chemical structure is highly responsible for their remarkable affinit y to the bone. The resulting biological effect of the various derivati ves, however, depends on the two substitutents attached to the central carbonic group. Therefore every single bisphosphonate demonstrates it s own specific chemical, physical, biological and therapeutical proper ties. The ''coupling'' of bone resorption and remodeling is in need of a complex interaction of many different factors. Known coupling signa ls of osteoclasts and osteoblasts are mainly TGF-beta, prostaglandine- E2 and IL-1. The osteoclast-activating factor (OAF) is related to a nu mber of cytokines as IL-1, TNF-alpha and TNF-beta, being able to stimu late the generation and stimulation of new as well as to activate pref ormed and mature osteoclasts. Cytokines, in return, stimulate the prod uction of prostaglandines representing as bone resorbing factors thems elves. Bone matrix factors stimulate the liberation of IL-1 from monoc ytes in a dose dependent mechanism. After treatment with bisphosphonat es this effect is diminished as a result of a reduced binding capacity of the monocytes. However, initially many bisphosphonates lead to a s timulation of collagenase and PGE(2) in chondrocytes meaning an enhanc ement of the IL-1 effect with transient protein shift expressing an ac ute phase reaction combined with fever and reduction of circulating ly mphocytes after the first application. After further repetitions of bi sphosphonate application these effects cease to occur, signifying that the effect is limited in time. The inhibiting power of a number of bi sphosphonates leads to a specific decrease in macrophage proliferation and migration not affecting other cell lines such as granulocytes. Mo reover, some bisphosphonates are able to cause a retardation of macrop hage-dependent lymphocyte proliferation. As another example, a reducti on in thymic maturation and an imbalance of T-cell function when apply ing bisphosphonates has been obseved. Scientific research in recent ye ars demonstrated that at the level of cellular compounds bisphosphonat es lead to complex changes in bone metabolism. Besides the individuall y quite variable mode of action of each distinct bisphosphonate time-d ependent phenomena, the locally achievable concentrations are also of outstanding importance. The diversity in character and performance of these compounds should not handicap further clinical trials. On the co ntrary, such a great variety opens up new chances to discover numerous facilities in the application of these very interesting bisphosphonat e compounds.