Intermittent parathyroid hormone (PTH) increases bone formation and prevents bone loss in hindlimb unloaded (HLU) rats. However, the mechanisms of action of PTH are incompletely known. To explore possible interactions between weight bearing and PTH, we treated six-month-old weight bearing and HLU rats with a human therapeutic dose (1 µg/kg/d) of human PTH (1-34) (hPTH). Cortical and cancellous bone formation was measured in tibia at the diaphysis proximal to the tibia-fibula synostosis and at the proximal metaphysis, respectively. Two weeks of hindlimb unloading resulted in a dramatic decrease in the rate of bone formation at both skeletal sites which was prevented by PTH treatment at the cancellous site only. In contrast, PTH treatment increased cortical as well as cancellous bone formation in weight bearing rats. Two-way ANOVA revealed that hPTH and HLU had independent and opposite effects on all histomorphometric indices of bone formation (MAR, dL.Pm and BFR) at both skeletal sites. The bone anabolic effects of weight bearing and hPTH on dL.Pm and BFR at the cortical site were additive as were the effects on MAR at the cancellous site. In contrast, weight bearing and hPTH resulted in synergistic increases in cortical bone MAR and cancellous bone dL.Pm and BFR. We conclude that weight bearing and PTH act cooperatively to increase bone formation by resulting in site specific additive and synergistic increases in indices of osteoblast number and activity, suggesting that weight bearing exercise targeted to osteopenic skeletal sites may improve the efficacy of PTH therapy for osteoporosis.