Mechanisms underlying the waning of osteoanabolic therapy effects in osteoporosis

Osteoanabolic therapies such as parathyroid hormone (PTH) analogs (teriparatide [TPT], abaloparatide [ABL]) 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 mo 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 (eg, sclerostin, DKK1), and mechanostatic feedback from increased bone mass. The contrasting kinetics of TPT, ABL, 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.