Osteoporosis pharmacotherapy is divided into two mechanistically distinct classes: antiresorptive agents (which slow osteoclast-mediated bone resorption) and anabolic agents (which stimulate osteoblast-mediated bone formation). Understanding their mechanisms is essential for optimal sequencing. Bisphosphonates (alendronate, risedronate, zoledronic acid) are the most widely prescribed antiresorptive agents. They bind avidly to hydroxyapatite on bone surfaces and are internalized by osteoclasts during resorption. Inside the osteoclast, nitrogen-containing bisphosphonates inhibit farnesyl pyrophosphate synthase in the mevalonate pathway, which is essential for prenylation of small GTPases (Ras, Rho, Rab) required for osteoclast cytoskeletal organization, membrane ruffling, and vesicular trafficking. This disruption triggers osteoclast apoptosis, reducing bone resorption by 50-70% and increasing BMD by 5-8% at the spine over 3 years. Denosumab (Prolia) is a fully human monoclonal antibody that binds RANKL, preventing its interaction with RANK on osteoclast precursors. By blocking the primary signal for osteoclast formation and activation, denosumab produces potent and reversible antiresorptive effects. Unlike bisphosphonates (which embed in bone matrix and persist for years), denosumab effects are fully reversible upon discontinuation, causing rapid rebound osteoclast activation and potentially catastrophic bone loss with multiple...