Parathyroid hormone (PTH) is an anabolic osteoporosis treatment that increases bone mass and reduces fracture risk. Clinically, the effects of PTH are site‐specific, increasing bone mass more at the spine than the hip and not increasing bone mass at the radius. Differences in local loading environment between the spine, hip, and radius may help explain the variation in efficacy, as PTH and mechanical loading have been shown to synergistically increase bone mass. We hypothesized that differences in loading mode might further explain these variations. Owing to the curvature of the mouse tibia, cyclic compression of the hindlimb causes bending at the tibial midshaft, placing the anterior surface under tension and the posterior surface under compression. We investigated the combination of PTH treatment and tibial loading in an osteoblast‐specific estrogen receptor‐alpha knockout mouse model of low bone mass (pOC‐ERαKO) and their littermate controls (LCs) and analyzed bone morphology in the tensile, compressive, and neutral regions of the tibial midshaft. We also hypothesized that pretreating wild‐type C57Bl/6J (WT) mice with PTH prior to mechanical loading would enhance the synergistic anabolic effects. Compression was more anabolic than tension, and PTH enhanced the effect of loading, particularly under compression. PTH pretreatment maintained the synergistic anabolic effect for longer durations than concurrent treatment and loading alone. Together these data provide insights into more effective physical therapy and exercise regimens for patients receiving PTH treatment. © 2022 American Society for Bone and Mineral Research (ASBMR).