Bisphosphonates influence the proliferation and the maturation of normal human osteoblasts

The key pharmacological action for the clinical use of bisphosphonates lies in the inhibition of osteoclast-mediated bone resorption. Osteoblasts could be other target cells for bisphosphonates. We studied the effects of bisphosphonates on the proliferation and the differentiation of normal human bone trabecular osteoblastic cells (hOB). We tested 4 different compounds: clodronate, pamidronate and 2 newer compounds: ibandronate, a nitrogen-containing bisphosphonate and zoledronate, which is a heterocyclic imidazole compound. Ibandronate and zoledronate stimulated hOB cell proliferation by up to 30% (p<0.05) after 72 h for concentrations ranging from 10(-8) M to 10(-5) M. Clodronate transiently enhanced hOB cell survival after only 24 h (+60%, p<0.001) whereas pamidronate had no effect. Longer time course studies, in presence of fetal calf serum, revealed that cell growth was finally reduced by all 4 bisphosphonates (40% after 7 days). Type I collagen synthesis was transiently increased by all 4 bisphosphonates after only 48 h incubation (+17% to +67%, p<0.05). Clodronate increased ALP activity by up to 1.7-fold after 4 days of culture (p<0.05) whereas ibandronate or zoledronate exhibited lesser stimulatory effects (+17 to +30%), and pamidronate had no significant effect. In conclusion, we found that different bisphosphonates, currently used or tested in various clinical conditions, transiently stimulated the growth of preosteoblastic cells and thereafter increased their differentiation according to sequential events (type I collagen synthesis first, then ALP activity to a lesser extent). Our data suggest that the beneficial effects of bisphosphonate treatment on bone mass and integrity could be partly mediated through a direct action on osteoblasts.