OSTEOCLAST ACTIVATION - POTENT INHIBITION BY THE BISPHOSPHONATE ALENDRONATE THROUGH A NONRESORPTIVE MECHANISM

Alendronate, an aminobisphosphonate used in the treatment of osteoporo sis, is a potent inhibitor of bone resorption. Its mechanism of action is unknown. Because it localizes to bone surfaces, we compared the se nsitivity of components of the resorptive process to incubation on ale ndronate-coated bone surfaces. We found that bone resorption by osteoc lasts isolated from neonatal rat bone was unaffected by alendronate (1 0(-4) M). Osteoclast production in bone marrow cultures, as assessed b y the production of calcitonin-receptor positive cells, was observed e ven at 10(-4) M, but bone resorption in these cultures was almost comp letely abolished by 10(-6) M alendronate. The greater sensitivity of o steoclast activation to inhibition by alendronate that these results s uggest was supported by similar inhibition of osteoblast-mediated acti vation of osteoclasts from neonatal rat bone. Thus, activation of oste oclasts by osteoblastic/stromal cells is apparently the most sensitive component of the pathway whereby bone resorption is affected. Moreove r, the ability of alendronate to suppress osteoclastic activation does not depend on resorption-mediated release of alendronate from bone su rfaces. This ability extends the range of cell types and processes tha t might be affected by alendronate, beyond those in the immediate vici nity of resorbing cells, to include any cell that comes into contact w ith alendronate-coated bone surfaces. (C) 1997 Wiley-Liss, Inc.