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A single CT-guided percutaneous intraosseous injection of thermosensitive simvastatin/poloxamer 407 hydrogel enhances vertebral bone formation in ovariectomized minipigs

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Abstract

Summary

The ultimate goal of osteoporosis treatment is prevention of fragile fracture. Local treatment targeting specific bone may decrease the incidence of osteoporotic fractures. We developed an injectable, thermosensitive simvastatin/poloxamer 407 hydrogel; a single CT-guided percutaneous intraosseous injection augmented vertebrae in ovariectomized minipigs.

Introduction

The greatest hazard associated with osteoporosis is local fragility fractures. An adjunct, local treatment might be helpful to decrease the incidence of osteoporotic fracture. Studies have found that simvastatin stimulates bone formation, but the skeletal bioavailability of orally administered is low. Directly delivering simvastatin to the specific bone that is prone to fractures may reinforce the target bone and reduce the incidence of fragility fractures.

Methods

We developed an injectable, thermosensitive simvastatin/poloxamer 407 hydrogel, conducted scanning electron microscopy, rheological, and drug release analyses to evaluate the delivery system; injected it into the lumbar vertebrae of ovariectomized minipigs via minimally invasive CT-guided percutaneous vertebral injection. Three months later, BMD, microstructures, mineral apposition rates, and strength were determined by DXA, micro-CT, histology, and biomechanical test; expression of VEGF, BMP2, and osteocalcin were analyzed by immunohistochemistry and Western blots.

Results

Poloxamer 407 is an effective controlled delivery system for intraosseous-injected simvastatin. A single injection of the simvastatin/poloxamer 407 hydrogel significantly increased BMD, bone microstructure, and strength; the bone volume fraction and trabecular thickness increased nearly 150 %, bone strength almost doubled compared with controls (all P < 0.01); and induced higher expression of VEGF, BMP2, and osteocalcin.

Conclusions

CT-guided percutaneous vertebral injection of a single simvastatin/poloxamer 407 thermosensitive hydrogel promotes bone formation in ovariectomized minipigs. The underlying mechanism appears to involve the higher expression of VEGF and BMP-2.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Project Nos. 81171693 and 81100895) and the National High Technology Research and Development Program of China (863 Program, Project No. SS2015AA020304).

Conflicts of interest

Jie Tan, Xin Fu, Chuiguo Sun, Chen Liu, Xianhua Zhang, Yueyi Cui, Qi Guo, Teng Ma, Hong Wang, Guohong Du, Xiaoxue Yin, Zhongjun Liu, HuijieLeng, YingshengXu, and Chunli Song declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, China

    J. Tan, X. Fu, C. G. Sun, Y. Y. Cui, T. Ma, H. Wang, G. H. Du, X. Yin, Z. J. Liu, H. J. Leng & C. L. Song

  2. Beijing Key Laboratory of Spinal Diseases, Beijing, 100191, China

    C. G. Sun, H. Wang, G. H. Du, X. Yin, Z. J. Liu, H. J. Leng & C. L. Song

  3. Department of Pharmacology, Peking University Third Hospital, Beijing, 100191, China

    X. H. Zhang

  4. Department of Radiology, Peking University Third Hospital, Beijing, 100191, China

    C. Liu

  5. Department of Neurology, Peking University Third Hospital, Beijing, 100191, China

    Q. Guo & Y. S. Xu

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  1. J. Tan
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  2. X. Fu
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  3. C. G. Sun
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  15. C. L. Song
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Correspondence to C. L. Song.

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Tan, J., Fu, X., Sun, C.G. et al. A single CT-guided percutaneous intraosseous injection of thermosensitive simvastatin/poloxamer 407 hydrogel enhances vertebral bone formation in ovariectomized minipigs. Osteoporos Int 27, 757–767 (2016). https://doi.org/10.1007/s00198-015-3230-y

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