Abstract Moving toward a goal-directed-treatment strategy in osteoporosis necessitates considering the opportunities and challenges associated with transitions in osteoporosis therapy. Some transitions are straightforward; transition from bone anabolic treatment to antiresorptives maintains or further improves the bone mineral density (BMD) increase and the antifracture effect obtained during treatment with a bone anabolic. Transitions from one antiresorptive to another are also, in most cases, safe and may lead to further increases in BMD if the transition is from an oral antiresorptive to a parentally administrated antiresorptive, such as zoledronate or denosumab. However, challenges arise when transitioning from antiresorptives to bone anabolic treatment, as the anabolic effect will be blunted compared to the effect seen in treatment-naïve patients, and transitions involving discontinuation of denosumab after more than 2 to 3 years of treatment. Sequential treatment of osteoporosis is needed for many patients to prevent fractures and obtain BMD levels associated with an acceptable fracture risk. While not all treatment transitions are optimal, the majority are safe, except for transitioning from denosumab to a bone anabolic agent or discontinuation of denosumab without appropriate follow-up treatment. These specific transitions should be avoided.