Oral Presentation ESA-SRB-APEG-NZSE 2022

Temporal changes in bone turnover and microarchitecture following withdrawal of RANKL inhibition (#92)

Albert S Kim 1 2 3 , Ariel Castro-Martinez 1 , Marija K Simic 1 3 , Jackie R Center 1 3 , Christian M Girgis 2 4 , Peter I Croucher 1 3 , Michelle M McDonald 1 3
  1. Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW, Australia
  3. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
  4. Faculty of Medicine & Health, University of Sydney, NSW 2600, Australia

Denosumab is an effective osteoporosis treatment, preventing bone loss by inhibiting RANKL. However, stopping denosumab leads to rebound bone mineral density(BMD) loss. This is due to accelerated bone resorption by osteoclasts. Serum bone turnover markers have been utilised to guide sequential therapy following denosumab discontinuation, however an optimal strategy has not been established. Understanding the temporal changes in osteoclast activity will guide safe, effective sequential therapy following denosumab discontinuation. We hypothesised that serum TRAP, a marker of enzymatic activity of osteoclasts, would be a more useful marker in this context.

Seven-week-old female C57BL/6 mice were treated with 2-weeks of thrice-weekly saline (vehicle) or OPG:Fc (10mg/kg) to inhibit RANKL. Longitudinal BMD and serum TRAP5b were measured throughout the study. Serum CTX and microCT were performed at weeks 2, 11 and 13.

Following OPG:Fc, BMD peaked at week 8 in treated mice and normalised to vehicle levels by week 13 (A). MicroCT analysis showed significantly higher trabecular volume (BV/TV) at the diaphysis in OPG:Fc treated mice at all timepoints (B).

Serum TRAP was significantly higher in treated mice at week 11 though serum CTX was equivalent to vehicle levels. Both serum TRAP and CTX were significantly higher in treated mice at week 13 by which bone loss had occurred and BMD reached vehicle levels (C). Longitudinally, serum TRAP was fully suppressed by week 2 and remained suppressed until week 8, following which serum TRAP levels rose 64% above vehicle levels at week 12. This rise in TRAP between weeks 8 to 10 preceded the decline in BMD (D).

Our findings show that rebound decline in BMD has already occurred by the time CTX rises above vehicle levels. A significant rise in serum TRAP occurs earlier and may be a better marker to guide sequential therapy following denosumab discontinuation.

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