Original Full Length ArticleSclerostin antibody prevented progressive bone loss in combined ovariectomized and concurrent functional disuse

- A novel concurrent mechanical unloading and OVX model was generated to characterize the effect of severe bone loss condition.
- The study is associated closely with post-menopause cohorts who are mechanically immobilized due to diseases or injury.
- HLS + OVX animals were significantly more osteoporotic due to the additive effect of concurrent unloading and ovariectomy.
- With short-term Scl-Ab inhibition, bone mass and strength were significantly improved to or beyond age-match control level.
- Scl-Ab prevented trabecular bone loss from HLS-induced, OVX-induced, and combined HLS + OVX induced osteoporosis.

Osteoporosis is characterized by low bone mass and compromised trabecular architecture, and is commonly occurred in post-menopausal women with estrogen deficiency. In addition, prolonged mechanical unloading, i.e., long term bed rest, can exaggerate the bone loss. Sclerostin is a Wnt signaling antagonist and acts as a negative regulator for bone formation. A sclerostin-neutralizing antibody (Scl-Ab) increased bone mineral density in women with postmenopausal osteoporosis and healthy men. The objective of this study was to characterize the condition of bone loss in ovariectomized (OVX) rats with concurrent mechanical unloading and evaluate the effect of sclerostin antibody treatment in mitigating the prospective severe bone loss conditions in this model. Four-month-old OVX- or sham-operated female SD rats were used in this study. They were subjected to functional disuse induced by hind-limb suspension (HLS) or free ambulance after 2 days of arrival. Subcutaneous injections with either vehicle or Scl-Ab at 25 mg/kg were made twice per week for 5 weeks from the time of HLS. μCT analyses demonstrated a significant decrease in distal metaphyseal trabecular architecture integrity with HLS, OVX and HLS + OVX (bone volume fraction decreased by 29%, 71% and 87% respectively). The significant improvements of various trabecular bone parameters (bone volume fraction increased by 111%, 229% and 297% respectively as compared with placebo group) with the administration of Scl-Ab are associated with stronger mechanical property and increased bone formation by histomorphometry. These results together indicate that Scl-Ab prevented the loss of trabecular bone mass and cortical bone strength in OVX rat model with concurrent mechanical unloading. The data suggested that monoclonal sclerostin-neutralizing antibody represents a promising therapeutic approach for severe osteoporosis induced by estrogen deficiency with concurrent mechanical unloading.