A three-dimensional dynamic in vitro bone remodeling model reveals multicellular effects of anti-osteoporotic agents.

Anti-osteoporotic drugs are effective in reducing fracture risk, yet their long-term management is frequently associated with paradoxical skeletal complications, the cellular basis of which remains poorly defined. Bone remodeling is a continuous process that depends on functional coupling between osteoclast-mediated bone resorption and mesenchymal stem cell (MSC)-driven bone formation. Using a three-dimensional dynamic in vitro system that preserves osteoclast activity on bone surfaces, we investigated how anti-osteoporotic agents modulate osteoclast-MSC interactions. We found that zoledronic acid suppressed osteoclast maturation and resorptive activity, while concurrently inhibiting MSC migration and subsequent osteoblastic differentiation. In contrast, teriparatide enhanced MSC recruitment and osteogenic differentiation but also accelerated the maturation of multinucleated osteoclasts and bone resorption. These findings indicate that both anti-resorptive and anabolic therapies exert complex multicellular effects that extend beyond their classical lineage-specific actions, leading to altered coupling dynamics during bone remodeling. Our study provides cellular insight into drug-associated skeletal side effects and establishes a functional platform for evaluating the multicellular impact of osteoporosis therapies.