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July 16th, 2025
Version: 2
University of Galway
molecular biology
biorxiv

Early intermittent low dose sclerostin antibody treatment promotes sur-face bone formation and reduces bone loss, but also decreases osteocyte apoptosis and mechanotransduction in ovariectomized rats

Naqvi, S. M.Open in Google Scholar•Ali Rizvi, S. W.Open in Google Scholar•Allison, H.Open in Google Scholar•O'Sullivan, L.Open in Google Scholar•Holdsworth, G.Open in Google Scholar•Panadero-Perez, J. A.Open in Google Scholar•Schiavi, J.Open in Google Scholar•McNamara, L. M.Open in Google Scholar

Neutralizing sclerostin antibodies mitigate bone loss and promote bone formation, thereby re-ducing fracture risk in postmenopausal osteoporosis. Clinically, this treatment targets women at high risk of fragility fractures years after menopause. However, bone loss occurs rapidly during early menopause, followed by longer-term changes in bone mineralization. These changes are associated with osteocyte apoptosis, perilacunar remodelling, and altered osteocyte mechano-sensitivity. The objective of this study was to evaluate the effects of early intermittent low-dose sclerostin antibody (Scl-Ab) therapy on: (1) osteoclastogenesis and bone resorption, (2) peri-lacunar remodelling, (3) secondary mineralization, and (4) osteocyte mechanosensitivity. Fe-male retired breeder Wistar rats underwent bilateral ovariectomy and received monthly low-dose Scl-Ab injections (2 mg/kg/month) from 3 to 14 weeks post-OVX, while a control group remained untreated. We report that early intermittent low-dose Scl-Ab treatment increased bone formation (calcein labelling) and reduced bone resorption, as evidenced by a decrease in TRAP+ osteoclasts and reduced expression of catabolic genes (Sost, Ctsk, Mmp9) compared to untreated rats. Treatment also decreased the percentage of empty lacunae and the number of MMP14+ osteocytes, indicating improved osteocyte survival and reduced perilacunar remodel-ling. Furthermore, the expression of osteocyte-mediated mineralization genes (DMP1, PHEX, OPN, ALP) was reduced. Nano-CT analysis revealed decreased perilacunar mineral density, along with smaller lacunae. Additionally, the expression of mechanotransduction-related genes (Vcl, integrins 5, V, {beta}1, CX43, Axin2, IFT88, Adcy6, Pkd1, Cav1) was also reduced. We propose that early intervention with intermittent low-dose Scl-Ab therapy can promote surface bone formation while attenuating osteocyte-mediated secondary mineralization following initial bone loss.

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