Reprogramming bone homeostasis: The recoupling-oriented framework of bidirectional regulation strategies for...

Current osteoporosis treatments reduce fracture risk by suppressing bone resorption, stimulating bone formation, or combining both effects. Yet these clinical benefits do not show whether formation has resumed at sites where bone was previously resorbed. This Review uses a remodeling recoupling framework to examine this resorption-to-formation transition. We define recoupling as restoration of the sequence from resorption through reversal to osteoblast recruitment and bone formation. This differs from bidirectional regulation, in which osteoblast activity increases and osteoclast activity decreases without evidence that the two responses are linked. We review the cellular communication, signaling pathways, cell-survival mechanisms, and systemic conditions that influence this transition. We also assess candidate targets and treatments according to the strength of clinical, human, animal, and mechanistic evidence. The available evidence is strongest for established therapies and several human-supported pathways, whereas many proposed targets and delivery approaches remain preclinical. This framework may help guide treatment sequencing, patient selection, bone-targeted delivery, and the development of measures that determine whether formation follows resorption.