Treatment of postmenopausal osteoporosis with bone-forming and antiresorptive treatments: Combined and sequential approaches.

Efficient therapies are available for the treatment of osteoporosis. Bisphosphonates and denosumab are the most commonly used antiresorptive therapies. Despite differences in the increase in bone mineral density seen with these drugs, the reductions in fracture risk are similar; 50-70%, 20%, and 40% for vertebral, non-vertebral and hip fractures, respectively. The bone-forming treatments; teriparatide and abaloparatide increase bone mineral density more than the antiresorptives and the reductions in fracture risk are 85% and 40-50% for vertebral and non-vertebral fractures, respectively, compared to placebo. The VERO study demonstrated a >50% reduction in vertebral and clinical fractures in women treated with teriparatide compared to risedronate. The dual-action treatment; romosozumab leads to more pronounced increases in BMD than other treatment modalities and reduces the risk of vertebral and clinical fractures by 73% and 36% compared to placebo after 12 months and the sequential treatment regime; romosozumab for 12 months followed by alendronate reduced the risk of vertebral, non-vertebral and hip fractures by 48%, 20% and 38%, respectively compared to alendronate after 2-3 years. The evidence for combination therapy targeting both resorption and formation is limited as only short-term studies with BMD as the endpoint have been performed. All bone-forming and dual-action treatments increase BMD and reduce the fracture risk, however, the effect wears off with time and treatment is therefore only temporary and should be followed by antiresorptive treatment with a bisphosphonate or denosumab. The sequence of treatment matters as the BMD response to teriparatide is reduced in patients previously treated with bisphosphonates; however, based on the findings of the VERO trial, the anti-fracture efficacy of bone-forming treatment in comparison with risedronate seems to be preserved after bisphosphonate therapy. The DATA study suggested that transitioning from denosumab to teriparatide is problematic due to the increase in bone resorption occurring after stopping denosumab. Studies have shown further improvements in BMD when transitioning from oral bisphosphonates to zoledronic acid or denosumab. Management of osteoporosis will in many patients include a long-term treatment plan. This will often include sequential therapy which in severe cases preferably should start with bone-forming followed by antiresorptive treatment. The severity of osteoporosis, reaching a treatment goal, and responding to treatment failure are important factors determining the treatment sequence in the individual patient.