Abstract
Osteoporosis is the most frequent systemic skeletal disorder characterized by an increased fracture risk and substantial global burden. While pharmacological therapies, including antiresorptive agents, anabolic agents, and dual-action agents, have demonstrated efficacy in reducing fracture risk and improving bone mineral density, long-term management remains challenging. Limitations, including treatment duration restrictions, safety concerns, rebound phenomena, and incomplete skeletal restoration, have shifted focus from prolonged monotherapy toward strategic therapeutic approaches integrating multiple agents over time. This narrative review examines current osteoporosis pharmacotherapy with emphasis on sequential and combination treatment strategies. Sequential therapy, involving strategic transitions between agents with complementary mechanisms, has emerged as optimal for maximizing and sustaining skeletal benefits. Evidence demonstrates that anabolic-to-antiresorptive sequences produce substantial bone mineral density gains and fracture risk reduction. Conversely, antiresorptive-to-anabolic transitions often result in transient bone loss and attenuated responses. Combination therapy, particularly teriparatide with denosumab, produces greater bone mineral density increases than monotherapy but remains limited by cost, uncertain fracture benefits, and potential cumulative toxicity. Current evidence supports goal-directed, individualized treatment strategies prioritizing sequencing based on fracture risk, prior therapies, and bone turnover status. Optimal regimens typically involve initial bone-forming therapy in high-risk patients, followed by antiresorptive consolidation. Future research should refine sequential protocols, identify predictive biomarkers, establish optimal durations, and conduct adequately powered fracture trials to validate strategic approaches over traditional monotherapy.