Early Intervention with Low-Dose Sclerostin Antibody Therapy can Reduce Osteocyte-mediated Secondary Mineralization after initial bone loss in Ovariectomised Rats

Neutralizing antibodies targeting sclerostin (Scl-Ab) mitigate bone loss and promote bone formation, thereby reducing fracture risk in postmenopausal osteoporosis. Clinical use of Scl-Ab is indicated for postmenopausal women with severe osteoporosis who are at high risk of, or have a history of, fragility fractures, which can occur many years after menopause. However, in early stages of estrogen deficiency there is rapid bone loss, which abates thereafter, whereas in the longer-term changes in bone mineralization occur. This study seeks to investigate whether administering intermittent low-dose monthly sclerostin antibody during early estrogen deficiency could mitigate osteoclastogenesis but also prevent osteocyte-driven secondary mineralization, due to apoptosis, perilacunar remodelling and osteocyte mechanosensitivity. Female Wistar rats that had completed their breeding cycles underwent bilateral ovariectomy as a model of postmenopausal osteoporosis. After 3 weeks of bone loss, one group received monthly low-dose Scl-Ab injections (2 mg/kg/month) and a control group remained untreated. We report that early treatment with intermittent low-dose Scl-Ab mildly increased bone formation, reduced TRAP+ osteoclasts and suppressed catabolic and matrix degradation gene expression (Sost, Ctsk, Mmp9) compared to untreated rats. There was a decrease in the percentage of empty lacunae and MMP14+ osteocytes, along with decreased gene expression associated with osteocyte-mediated mineralization (DMP1, PHEX, OPN, ALP) and mechanotransduction (Vcl, integrins α5, αV, β1, CX43, Axin2, IFT88, Adcy6, Pkd1, and Cav1). Thus, we propose that early intervention with intermittent low-dose Scl-Ab therapy can promote surface bone formation but reduce osteocyte-mediated secondary mineralization after initial bone loss.