Bisphosphonates (BPN) are potent inhibitors of bone resorption with suggested dose dependent effects on osteoblasts. Fluoride (F) is an anabolic agent capable of increasing bone mass and, depending upon genetic background, stimulates osteoclastogenesis. This study aimed to investigate BPN and F's in vivo effects on bone marrow derived osteoprogenitor cells. Mice from the C3H/HeJ (C3H), C57BL/6J (B6), FVB/NJ (FVB) and BALB/cByJ (BALB-c) strains were treated for 3-weeks with 0, 3, 30, or 150 mcg/kg/week alendronate (ALN) administered s.c. alone or in combination with 50ppm fluoride (F). Bone marrow cells were harvested and subjected to in vitro CFU-F and CFU-OB assays. Results showed strain dependent baseline differences in CFU-F, CFU-OB/ALP+, and CFU-OB/total. ALN and F treatments resulted in strain specific responses for CFU-F, CFU-OB/ALP+, and CFU-OB/total. No dose responses to ALN were observed. Genetic factors appear to play a role in ALN's effects on CFU-F and CFU-OB/total, but not on CFU-OB/ALP+