Osteoporosis is a disease characterized by decreased bone mass and increased risk of fracture. Methods of increasing bone mass include applied mechanical loading and pharmaceutical treatments such as parathyroid hormone (PTH). Decreased bioavailable estrogen is a major contributor to bone loss with age and may alter the responses to loading or PTH. Understanding how these factors influence each other is important for the prevention and treatment of osteoporosis.In bone, estrogen signals primarily through estrogen receptor-alpha (ER_), which has also been implicated in bone’s response to mechanical loading. However, ER_’s role in specific bone cells is less clear, particularly with age. We developed osteoblast-specific ER_ knockout (pOC-ER_KO) mice and applied cyclic tibial compression to adult 26-week-old female and male mice. Female pOC-ER_KO mice had reduced cancellous and cortical bone mass but males had normal bone mass. Adult female mice had greatly reduced responses to loading than young mice, even at higher load magnitudes, but males retained loading responses with age. PTH and mechanical loading have been shown to have synergistic anabolic skeletal effects. We hypothesized that the effects would differ by applied loading modality, tension or compression. We analyzed human femoral neck samples from PTH-treated patients receiving total hip replacements. Under normal activity, the femoral neck experiences bending, with the superior side under tension and the inferior side under compression. PTH was more effective at increasing bone formation parameters in older, low body mass, female patients on the tensile surface of the femoral neck. We also investigated the effect of loading modality on PTH in 10- and 16-week-old female pOC-ER_KO mice using tibial compression, which induces bending at the midshaft due to the curvature of the mouse tibia. PTH increased the anabolic response of the mid-diaphysis in regions of applied compression more than applied tension. Lack of ER_ did not influence the relationship between PTH and loading. Additionally, pre-treatment with PTH prior to tibial loading in 16-week-old female C57Bl/6J mice increased the cortical and cancellous response to loading more than concurrent treatment alone.