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Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength

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Abstract

Summary

This study was to determine if antibody against sclerostin (Scl-Ab) could prevent glucocorticoid (GC)-induced osteoporosis in mice. We found that Scl-Ab prevented GC-induced reduction in bone mass and bone strength and that the anabolic effects of Scl-Ab might be partially achieved through the preservation of osteoblast activity through autophagy.

Introduction

Glucocorticoids (GCs) inhibit bone formation by altering osteoblast and osteocyte cell activity and lifespan. A monoclonal antibody against sclerostin, Scl-Ab, increased bone mass in both preclinical animal and clinical studies in subjects with low bone mass. The objectives of this study were to determine if treatment with the Scl-Ab could prevent loss of bone mass and strength in a mouse model of GC excess and to elucidate if Scl-Ab modulated bone cell activity through autophagy.

Methods

We generated reporter mice that globally expressed dsRed fused to LC3, a protein marker for autophagosomes, and evaluated the dose-dependent effects of GCs (0, 0.8, 2.8, and 4 mg/kg/day) and Scl-Ab on autophagic osteoblasts, bone mass, and bone strength.

Results

GC treatment at 2.8 and 4 mg/kg/day of methylprednisolone significantly lowered trabecular bone volume (Tb-BV/TV) at the lumbar vertebrae and distal femurs, cortical bone mass at the mid-shaft femur (FS), and cortical bone strength compared to placebo (PL). In mice treated with GC and Scl-Ab, Tb-BV/TV increased by 60–125 %, apparent bone strength of the lumbar vertebrae by 30–70 %, FS-BV by 10–18 %, and FS-apparent strength by 13–15 %, as compared to GC vehicle-treated mice. GC treatment at 4 mg/kg/day reduced the number of autophagic osteoblasts by 70 % on the vertebral trabecular bone surface compared to the placebo group (PL, GC 0 mg), and GC + Scl-Ab treatment.

Conclusions

Treatment with Scl-Ab prevented GC-induced reduction in both trabecular and cortical bone mass and strength and appeared to maintain osteoblast activity through autophagy.

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Acknowledgments

This work was funded by a research grant to UC Davis by Amgen and National Institutes of Health grant R01 AR061366 (to WY) and K24 AR04884, P50 AR060752, P50 AR063043, and R01 AR043052 (to NEL).

Conflicts of interest

Wei Yao, Weiwei Dai, Li Jiang, Evan Yu-An Lay, Zhendong Zhong, Robert O. Ritchie and Nancy Lane declare that they have no conflict of interest. Xiaodong Li and Huazhu Ke were employees of Amgen at the time when the study was performed.

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Correspondence to W. Yao.

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W. Yao and W. Dai contributed equally to this work.

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Yao, W., Dai, W., Jiang, L. et al. Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. Osteoporos Int 27, 283–294 (2016). https://doi.org/10.1007/s00198-015-3308-6

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