Effect of alendronate treatment on the osteoclastogenic potential of bone marrow cells in mice.

Bisphosphonates suppress bone resorption by inhibiting the activity of mature osteoclasts as well as the formation of osteoclasts from bone marrow-derived precursor cells. It is not yet known at which level of osteoclast development this latter action is exerted and whether this is due to a systemic effect of circulating bisphosphonate or to an action at the bone surface, given the property of these compounds to concentrate specifically at active bone sites. We addressed these questions in an ex vivo study in mice. The animals were treated with the bisphosphonate alendronate for various periods, and the central compartment of the bone marrow was isolated and cultured together with osteoclast-free fetal mouse bone explants. In this way the capacity of bone marrow cells, exposed previously to alendronate in vivo, to generate osteoclasts and induce resorption in vitro was examined. Alendronate (0.25 mg/kg, subcutaneously) given to mice for periods up to 4 weeks suppressed bone resorption, as expected, but did not affect the capacity of bone marrow cells to develop into mature osteoclasts and resorb the calcified matrix of bone explants. In addition, using monoclonal antibodies specific for different macrophage-granulocyte precursor subsets, we found that alendronate treatment did not affect the pattern of antigen expression of bone marrow cells, which is in line with the lack of an effect of the bisphosphonate on the ability of bone marrow cells to induce resorption in vitro. In contrast, in control experiments, lipopolysaccharide (0.1 mg) treatment induced marked changes in the pattern of antigen expression of bone marrow cells. In conclusion, our studies demonstrate that the inhibition of bone resorption by alendronate does not involve alteration of the osteoclastogenic potential of osteoclast progenitors (precursors) from the central bone marrow compartment. Moreover, this treatment did not alter the expression of markers specific for monocyte-macrophage precursors as well as mature macrophages. These results suggest that the effects of alendronate are exerted at the bone surface at late osteoclast precursors (and mature osteoclasts).