Early observations and pilot data that first suggested a new direction
Bisphosphonates dominated osteoporosis treatment for decades, but accumulating evidence suggested that patients with severe osteoporosis might benefit more from anabolic agents as initial therapy. The VERO trial provided the first head-to-head fracture endpoint comparison between an anabolic agent and an antiresorptive, randomizing 1,360 postmenopausal women with severe osteoporosis to teriparatide versus risedronate. Teriparatide reduced new vertebral fractures by 56% (risk ratio 0.44) and clinical fractures by 52% (HR 0.48), establishing that treatment selection mattered substantially for high-risk patients.
Landmark RCTs and pivotal trials that established the evidence base
The FRAME trial demonstrated the fracture-reducing potential of romosozumab, a sclerostin inhibitor with dual anabolic and antiresorptive action. Among 7,180 postmenopausal women, romosozumab reduced new vertebral fractures by 73% at 12 months compared with placebo (0.5% vs 1.8%; p<0.001). Crucially, the trial showed that patients who received romosozumab first followed by denosumab maintained superior fracture protection, establishing the concept of sequential anabolic-to-antiresorptive therapy.
Follow-up studies, subgroup analyses, and real-world validation
The critical challenge of treatment transitions emerged as denosumab discontinuation was associated with rapid bone loss and rebound vertebral fractures. The SHOTZ study and related trials examined whether zoledronic acid could prevent bone mineral density loss after denosumab cessation. Evidence showed that a single infusion of zoledronic acid did not fully prevent BMD loss at the lumbar spine, though hip BMD was partially preserved. This highlighted the need for careful planning of treatment transitions and the concept of treatment sequencing as central to osteoporosis management.
Integration into clinical practice guidelines and recommendations
The Endocrine Society 2020 guidelines and the AACE 2020 guidelines both incorporated the concept of treatment sequencing, recommending anabolic-first therapy for patients at very high fracture risk. Guidelines recognized that initiating treatment with an anabolic agent followed by an antiresorptive produces greater bone density gains and fracture reduction than the traditional antiresorptive-first approach. The importance of transition planning, particularly after denosumab, became a key guideline focus.
Endocrine Society
Anabolic therapy (teriparatide or romosozumab) recommended as initial treatment for patients at very high fracture risk, followed by antiresorptive consolidation
AACE
Sequential therapy with anabolic agent first for very high-risk patients; mandatory transition to antiresorptive after denosumab to prevent rebound bone loss
Now
Current standard of care and ongoing research directions
Osteoporosis treatment has shifted from a one-size-fits-all antiresorptive approach to a risk-stratified, sequenced strategy. For patients at very high fracture risk, an anabolic-first approach followed by antiresorptive consolidation is now standard of care. The critical importance of treatment transition planning is well recognized, particularly the need for bisphosphonate bridging after denosumab discontinuation. Remaining questions include optimal duration of anabolic therapy, best transition protocols, and whether re-treatment with anabolic agents is effective after an antiresorptive interval.
Why is anabolic-first therapy recommended for high-risk patients?+
The VERO trial showed teriparatide reduced vertebral fractures by 56% compared to risedronate, and the FRAME trial showed romosozumab reduced vertebral fractures by 73% versus placebo at 12 months. Starting with bone-building (anabolic) therapy and then transitioning to antiresorptive consolidation produces greater bone density gains and fracture reduction than the reverse sequence.
What happens when denosumab is stopped?+
Denosumab discontinuation is associated with rapid bone turnover rebound, bone density loss, and increased risk of multiple vertebral fractures. Transitioning to a bisphosphonate (typically zoledronic acid) is recommended, though studies including SHOTZ showed this does not fully prevent lumbar spine BMD loss. Careful planning of the transition is essential.
