Bisphosphonates are well known potent inhibitors of osteoclast activity and are widely used to treat
metabolic bone diseases. Recent evidence from in vitro and in vivo studies indicates that
bisphosphonates may additionally promote osteoblastic bone formation. In this study, we evaluated the effects of three FDA-approved and clinically utilized
bisphosphonates, on the proliferation and osteogenic differentiation of human bone marrow stromal cells (BMSC). BMSC were obtained from patients undergoing primary
total hip arthroplasty for end-stage degenerative
joint disease. Cells were treated with or without a
bisphosphonate (
alendronate,
risedronate, or
zoledronate) and analyzed over 21 days of culture. Cell proliferation was determined by direct cell counting. Osteogenic differentiation of BMSC was assessed with
alkaline phosphatase bioassay and gene expression analyses using conventional RT-PCR as well as real-time quantitative RT-PCR. All
bisphosphonates tested enhanced the proliferation of BMSC after 7 and 14 days of culture. Steady-state
mRNA levels of key genes involved in osteogenic differentiation such as bone morphogenetic protein-2 (BMP-2),
bone sialoprotein-II,
core-binding factor alpha subunit 1 (cbfa1) and
type 1 collagen, were generally increased by
bisphosphonate treatment in a type- and time-dependent manner. Gene expression levels varied among the different donors. Enhancement of osteogenic differentiation was most pronounced after 14 days of culture, particularly following
zoledronate treatment (p < 0.05 for BMP-2). In conclusion, using a clinically relevant in vitro model we have demonstrated that
bisphosphonates enhance proliferation of BMSC and initiate osteoblastic differentiation. When administered around
joint replacements,
bisphosphonates may potentially compensate for the deleterious effects of particulate wear debris at the
bone-implant interface, by encouraging increased numbers of cells committed to the osteoblastic phenotype, and thus improve the longevity of
joint replacements.