Osteoporosis is a skeletal disorder characterized by compromised bone strength, predisposing patients to an increased risk of fracture. Antiresorptive agents such as oral bisphosphonates are the standard treatment for postmenopausal osteoporosis, in conjunction with non-pharmacologic measures. Other treatment options include an intravenous bisphosphonate (zoledronic acid), a monoclonal antibody (denosumab), a bone-forming agent (teriparatide), and a selective estrogen receptor modulator (raloxifene). This systematic review was undertaken following a request from provincial drug formularies to evaluate the clinical effectiveness and harms of three of these agents, denosumab, raloxifene, and zoledronic acid, in postmenopausal women with osteoporosis.