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 two groups: 15 treated with denosumab (mean duration 4 years, range 6 months-9 years) and 15 treatment-naïve controls. Peripheral blood mononuclear cells (PBMCs) 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 (FACS). 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 to 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.
Keywords: Denosumab; Osteoclast precursors; Osteoporosis; Overshoot.
Denosumab is an anti-osteoporotic medication that has proven effective in preventing bone loss and reducing the incidence of fractures. When it is discontinued, there is a risk of overshoot in markers of bone turnover, which may lead to a reduction in bone mineral density and new vertebral fractures. Whilst we suspect the mechanism underlying this phenomenon, we do not know the process in any detail in terms of the cells involved, particularly the role of the progenitors of bone cells that break down bone tissue (osteoclast precursors). We found that in postmenopausal women treated with denosumab, there is an increase in one of the populations of osteoclast precursors. On denosumab discontinuation, accumulated cells can mature into osteoclasts, which remove bone and lead to the overshoot of bone turnover and decreased bone density.
© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.