Osteoanabolic therapies such as parathyroid hormone (PTH) analogs (teriparatide, abaloparatide) and the sclerostin inhibitor romosozumab rapidly stimulate new bone deposition but their bone-building effects are not indefinite. Clinical trials including bone turnover markers and bone histomorphometry studies show that the initial gains in bone formation and density wane with continued therapy - typically within 12-18 months for PTH analogs and even sooner for romosozumab. This invited review explores the biological mechanisms that may explain this waning response, including receptor desensitization at the PTH1 receptor level, depletion or saturation of bone-forming surfaces, exhaustion or downregulation of osteoblast progenitors, upregulation of endogenous Wnt pathway antagonists (e.g. sclerostin, DKK1), and mechanostatic feedback from increased bone mass. The contrasting kinetics of teriparatide, abaloparatide and romosozumab are compared, highlighting how their modes of action (remodeling- vs. modeling-based formation) influence the duration of anabolic activity. Finally, potential strategies to extend or rekindle anabolic effects are discussed - including sequential and combination therapies and adjunctive mechanical loading - with a view toward maximizing bone gains and reducing fracture risk. Understanding why anabolic drug efficacy attenuates provides insight into bone biology and guides the design of regimens to achieve more sustained increases in bone mass and strength.

Plain language summary : Osteoporosis drugs that build bone, like teriparatide, abaloparatide, and romosozumab, work very well at first – but their bone-building power fades with time. In this article, we explain why this happens. The bone’s own feedback system starts to slow down the building process after a while, due to factors like fewer active bone surfaces and natural inhibitors that the body produces. We also discuss new ideas to keep these treatments working longer, such as using drug combinations or exercise. This could help patients gain more bone and stay fracture-free for longer.© The Author(s) 2026.