Romosozumab treatment results in a transient early increase in bone formation and sustained decrease in bone resorption. Histomorphometric analyses revealed that the primary bone-forming effect of romosozumab is transient early stimulation of modeling-based bone formation on cancellous and endocortical surfaces; preclinical studies have demonstrated that romosozumab may affect changes in the remodeling unit resulting in positive bone balance. To further investigate the effects of romosozumab on bone balance, month 12 (M12) and M2 (to analyze early effects) unpaired bone biopsies from the FRAME clinical trial were analyzed using remodeling site reconstruction to assess whether positive changes in bone balance on cancellous/endocortical surfaces may contribute to the progressive improvement in bone mass/structure and reduced fracture risk in osteoporotic women at high fracture risk. At M12, bone balance was higher with romosozumab vs placebo on cancellous (+6.1μm vs +1.5μm; p =0.012) and endocortical (+5.2μm vs -1.7μm; p =0.02) surfaces; higher bone balance was due to lower final erosion depth (40.7μm vs 43.7μm; p =0.05) on cancellous surfaces and higher completed wall thickness (50.8μm vs 47.5μm; p =0.037) on endocortical surfaces. At M2, final erosion depth was lower on the endocortical surfaces (42.7μm vs 50.7μm; p =0.021) and slightly lower on the cancellous surfaces (38.5μm vs 44.6μm; p =0.11) with romosozumab vs placebo. Sector analysis of early endocortical formative sites revealed higher osteoid thickness (29.9μm vs 19.2μm; p = 0.005) and mineralized wall thickness (18.3μm vs 11.9μm; p =0.004) with romosozumab vs placebo. These evolving bone packets may reflect early stimulation of bone formation that contributes to the increase in completed wall thickness at M12. These data suggest that romosozumab induces a positive bone balance due to its effects on bone resorption and formation at the level of the remodeling unit, contributing to the positive effects on bone mass, structure, and fracture risk.