Osteoporosis is a chronic disease that requires life-long strategies to reduce fracture risk. Few trials have investigated the balance of benefits and risk with long-term use of osteoporosis therapies, and fewer still have investigated the consequences of treatment discontinuation. The best available evidence suggests that up to 10 years of treatment with an oral bisphosphonate maintains the degree of fracture risk reduction observed in the 3-year registration trials. With denosumab, 10 years of therapy appears to provide fracture risk reduction similar to or better than that observed in the 3-year registration trial. Available data suggest an increasing but low risk of fractures with atypical features with increasing duration of bisphosphonate therapy. Published data linking duration of therapy to osteonecrosis of the jaw are lacking for bisphosphonates and denosumab. Other side effects associated with denosumab or bisphosphonates do not appear to be related to therapy duration. The antifracture benefits of long-term therapy with bisphosphonates and denosumab in appropriately selected patients outweigh the low risk of serious side effects.