Je. Baier, BISPHOSPHONATES-CELLULAR MODE OF ACTION - INFLUENCE ON MEDIATORS WITHIN THE IMMUNE-SYSTEM, Tumordiagnostik & Therapie, 16(4), 1995, pp. 128-133
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.