Revisiting the activate depress free and repeat (ADFR) paradigm: Clinical use of cyclic romosozumab

Osteoporosis treatment does not normalize BMD. We hypothesized cyclic romosozumab dosing might provide greater BMD increases. Cyclic therapy (six romosozumab monthly doses then one denosumab dose) produced broadly similar BMD increases as previously reported for 12 romosozumab doses. A second cycle further increased spine and hip BMD but with a blunted response.

Evaluating novel osteoporosis medication approaches to maximize BMD is reasonable. A bone remodeling-based cyclic approach, i.e., activate, depress, free and repeat (ADFR), has been proposed. We hypothesized that short course romosozumab followed by denosumab represents an appropriate cycle. This exploratory retrospective case series reports six months of romosozumab treatment then one denosumab dose, followed by a second identical cycle.

Women at very high fracture risk were offered cyclic therapy. DXA was obtained at baseline, 1 and 2 years. Data from 41 women treated for 1, and 18 for 2 years are reported. Percent BMD change from baseline was evaluated by ANOVA.

Patient mean (SD) age and BMI were 68.8 (6.6) years and 25.6 (5.0) kg/m² respectively. Mean total hip T-score was -2.5, FRAX estimated hip fracture risk was 6.9%. After one cycle, mean ± SEM% BMD increase (all p < 0.001) from baseline at the lumbar spine (LS), total hip (TH) and femur neck (FN) was 12.6 ± 1.1%, 5.9 ± 0.8% and 4.4 ± 0.9% respectively. In 18 women completing a second cycle, BMD further increased to + 17.5% and + 8.7% at LS and TH, respectively. In a subset (n = 14) CTX was reduced from baseline (mean -78%) before cycle two with 11 below the lower limit of normal.

At one year, six monthly romosozumab doses then one denosumab dose substantially increased BMD. A second cycle further increased LS and TH BMD, but the response was blunted perhaps reflecting persistent turnover suppression by denosumab. Evaluation of novel romosozumab dosing approaches is indicated.