STRUCTURALLY DIFFERENT BISPHOSPHONATES EXERT OPPOSING EFFECTS ON ALKALINE-PHOSPHATASE AND MINERALIZATION IN MARROW OSTEOPROGENITORS

Bisphosphonates (BPs) are inhibitors of bone resorption and soft tissu e calcification. The biological effects of the BPs in calcium-related disorders are attributed mainly to their incorporation in bone, enabli ng direct interaction with osteoclasts and/or osteoblasts through a va riety of biochemical pathways. Structural differences account for the considerable differences in the pharmacological activity of BPs. We co mpared the effects of two structurally different compounds, alendronat e and imethylaminopyrazinio)ethylidene-1,1-bisphosphonic acid betaine (VS-6), in an osteoprogenitor differentiation system. The BPs were exa mined in a bone marrow stromal-cell culture system, which normally res ults in osteoprogenitor differentiation. The drugs were present in the cultures from days 2 to 11 of osteogenic stimulation, a period estima ted as being comparable to the end of proliferation and the matrix-mat uration stages. We found that the two different BPs have opposing effe cts on specific alkaline phosphatase (ALP) activity, on stromal-cell p roliferation, and on cell-mediated mineralization. These BPs different ially interact with cell-associated phosphohydrolysis, particularly at a concentration of 10(-2) of ALP K-m, in which alendronate inhibits w hereas VS-6 did not inhibit phosphatase activity. VS-6 treatment resul ted in similar and significantly increased mineralization at 10 and 1 mu M drug concentrations, respectively. In contrast, mineralization wa s similar to control, and significantly decreased at 10 and 1 mu M dru g concentrations, respectively, under alendronate treatment. (C) 1998 Wiley-Liss, Inc.