Reduced Osteoclastogenesis and RANKL Expression in Marrow from Women Taking Alendronate

Alendronate (AL) is commonly used for the prevention and treatment of osteoporotic fractures. Little is known about the effects of AL administration on osteoclast differentiation from human marrow progenitor cells. We used marrow discarded during orthopedic surgery to test the hypothesis that cultures of bone marrow-derived stem cells (BMCs) from subjects receiving AL (+AL) may differ from control subjects with respect to in vitro osteoclast differentiation and regulatory factors. The number of osteoclasts generated in BMC cultures from control subjects was 4.7-fold greater than that from +AL subjects (P = 0.015). RANKL expression in +AL BMCs was 57% of that in controls (P = 0.001), and OPG expression in +AL BMCs was greater than in controls (153%, P = 0.01). The mean RANKL/OPG ratio in BMCs was 0.65 +/- A 0.35 for +AL specimens and 1.28 +/- A 0.53 for controls (P = 0.031). In addition, we assessed the direct effect of AL on expression of RANKL and OPG in marrow stromal cells isolated from nine control women. Treatment with AL downregulated RANKL expression and upregulated OPG expression, with an average 50% decrease in RANKL/OPG ratio at 10(-7) M (P = 0.004). These results show that osteoclast differentiation is dysregulated in marrow isolated from +AL subjects. Furthermore, AL may inhibit human osteoclastogenesis by affecting the key regulatory genes in marrow cells.