Current anti-osteoporotic pharmacological treatments reduce fracture risk in part by altering bone remodeling/modeling. These effects can manifest on any or all of the bone envelopes—periosteal, intracortical, and trabecular/endocortical—each of which has unique effects on the biomechanical properties of bone. The purpose of this review is to provide an overview of how the most common FDA-approved anti-osteoporosis agents [bisphosphonates, estrogen/hormone replacement therapy, selective estrogen receptor modulators (SERMs), and parathyroid hormone (PTH)] affect tissue-level remodeling/modeling on each of the bone surfaces. Iliac crest biopsy data, the only means of assessing surface-specific bone formation in humans, exist for all of these agents although they predominately focus on trabecular/endocortical surfaces. Data from pre-clinical animal models provide an essential complement to human studies, particuarily for changes on periosteal surfaces and within the intracortical envelope. Although all of the anti-catabolic agents (estrogen replacement therapy, SERMs, bisphosphonates) exert positive effects on the various bone surfaces, the bisphosphonates produce the unique biomechanical combination of allowing normal periosteal expansion while limiting remodeling-induced bone loss on intracortical and trabecular/endocortical surfaces. PTH, the only FDA-approved anabolic agent, exerts biomechanically favorable alterations though enhanced trabecular/endocortical surface activity while also stimulating periosteal expansion. Through understanding how current and future anti-osteoporotic agents influence surface-specific bone activity we will move one step closer to developing agents that could potentially target a particular bone surface.