The effects of denosumab on osteoclast precursors in postmenopausal women: a possible explanation for the overshoot phenomenon after discontinuation

Upon denosumab discontinuation, an observed overshoot phenomenon in bone turnover may occur, potentially leading to a reduction in bone mineral density and the occurrence of vertebral fractures. Several theories have been proposed to explain this phenomenon, one of which is that osteoclast precursors might be accumulating during treatment. Our aim was to study the effects of denosumab on osteoclast precursors in postmenopausal women. This cross-sectional observational study included 30 postmenopausal women with osteopenia or osteoporosis, divided into 2 groups: 15 treated with denosumab (mean duration 4 years, range 6 months-9 years) and 15 treatment-naïve controls. Peripheral blood mononuclear cells were isolated from whole blood and were stained for CD14, MCSFR, CD11b, and TNFRII. Osteoclast precursors (CD14+/MCSFR+, CD14+/CD11b + OR CD14+/TNFRII+) were identified with fluorescent activated cell sorting. The proportion of osteoclasts was determined by calculating their percentage of the total cell population in each whole blood sample. To confirm the expected suppression of bone turnover in the subjects treated with denosumab, we measured serum PINP, CTX, and TRACP5b. Denosumab-treated patients exhibited a significantly higher count of CD14+/CD11b + osteoclast precursors compared with controls (median 4% vs 0.75%, p=.011). There was no correlation with the duration of treatment. Bone turnover markers were significantly lower in the group treated with denosumab than controls. Our findings indicate an increase in osteoclast precursors, which could explain the overshoot phenomenon observed after discontinuing denosumab.