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Sclerostin Antibody Reverses the Severe Sublesional Bone Loss in Rats After Chronic Spinal Cord Injury

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Abstract

To date, no efficacious therapy exists that will prevent or treat the severe osteoporosis in individuals with neurologically motor-complete spinal cord injury (SCI). Recent preclinical studies have demonstrated that sclerostin antibody (Scl-Ab) can prevent sublesional bone loss after acute SCI in rats. However, it remains unknown whether sclerostin inhibition reverses substantial bone loss in the vast majority of the SCI population who have been injured for several years. This preclinical study tested the efficacy of Scl-Ab to reverse the bone loss that has occurred in a rodent model after chronic motor-complete SCI. Male Wistar rats underwent either complete spinal cord transection or only laminectomy. Twelve weeks after SCI, the rats were treated with Scl-Ab at 25 mg/kg/week or vehicle for 8 weeks. In the SCI group that did not receive Scl-Ab, 20 weeks of SCI resulted in a significant reduction of bone mineral density (BMD) and estimated bone strength, and deterioration of bone structure at the distal femoral metaphysis. Treatment with Scl-Ab largely restored BMD, bone structure, and bone mechanical strength. Histomorphometric analysis showed that Scl-Ab increased bone formation in animals with chronic SCI. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increased Tcf7, ENC1, and the OPG/RANKL ratio expression, and decreased SOST expression. Our findings demonstrate for the first time that Scl-Ab reverses the sublesional bone loss when therapy is begun after relatively prolonged spinal cord transection. The study suggests that, in addition to being a treatment option to prevent bone loss after acute SCI, sclerostin antagonism may be a valid clinical approach to reverse the severe bone loss that invariably occurs in patients with chronic SCI.

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Abbreviations

SCI:

Spinal cord injury

SOST :

Sclerostin

Scl-Ab:

Sclerostin antibody

BMD:

Bone mineral density

MOI:

Moment of inertia

FEA:

Finite element analysis

BFR:

Bone formation rate

MS/BS:

Mineralizing surface/bone surface

DXA:

Dual-energy X-ray absorptiometer

PFA:

Paraformaldehyde

CFU-F:

Colony-forming unit-fibroblastic

CFU-ob:

Colony-forming unit-osteoblastic staining

MSC:

Mesenchymal stem cells

TRAP:

Tartrate-resistant acid phosphatase

H&E:

Hematoxylin and eosin

CTX:

Serum C-terminal telopeptide of Type I collagen

CTR:

Calcitonin receptor

BV:

Bone volume

TV:

Tissue volume

Tb.N:

Trabecular number

Tb.Th:

Trabecular thickness

Tb.Sp:

Trabecular separation

Conn.D:

Connectivity density

SMI:

Structure model index

OV:

Osteoid volume

OS:

Osteoid surface

N. Oc:

Osteoclast number

Pm:

Perimeter

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Acknowledgements

This work was supported by the Veterans Health Administration, Rehabilitation Research and Development Service (Grants 5I01RX001313, 5I01RX02089-A2, and 5I01RX000687 to WQ; B9212-C and B2020-C to WAB). Amgen Inc. and UCB Pharma provided Scl-Ab.

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Author notes

  1. Michael S. Ominsky

    Present address: Radius Health, Inc., 950 Winter St, Waltham, MA, 02451, USA

Authors and Affiliations

  1. National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA

    Wei Zhao, Yuanzhen Peng, Yiwen Qin, Jiangping Pan, Christopher Cardozo, William A. Bauman & Weiping Qin

  2. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Wei Zhao, Christopher Cardozo, William A. Bauman & Weiping Qin

  3. Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Christopher Cardozo

  4. Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    William A. Bauman

  5. Amgen Inc., Thousand Oaks, CA, USA

    Xiaodong Li & Michael S. Ominsky

  6. Indiana University Purdue University Indianapolis, Indianapolis, IN, USA

    Jiliang Li & Aihua Xu

  7. Baylor College of Dentistry, TX A&M, Dallas, TX, USA

    Jian Q. Feng

  8. UCB Pharma, Slough, UK

    Hua Zhu Ke

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  1. Wei Zhao
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  2. Xiaodong Li
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Contributions

WZ, XL, HK, WAB, and WQ were responsible for study design and data analysis. WZ, XL, YP, JP, JL, AX, YQ, JF, and CPC conducted the study. The manuscript was written by WZ and WQ and was revised and approved by all authors. WQ takes responsibility for the integrity of the data analysis.

Corresponding author

Correspondence to Weiping Qin.

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Conflict of interest

Wei Zhao, Yuanzhen Peng, Yiwen Qin, Jianping Pan, Jiliang Li, Aihua Xu, Jian Q. Feng, William A. Bauman, Christopher Cardozo, and Weiping Qin declare that they have no conflict of interest. XL is current employee and shareholder of Amgen Inc. MSO is an ex-Amgen employee and owns Amgen stocks, and HZK is current employee of UCB Pharma and shareholder of UCB Pharma and Amgen.

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All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Zhao, W., Li, X., Peng, Y. et al. Sclerostin Antibody Reverses the Severe Sublesional Bone Loss in Rats After Chronic Spinal Cord Injury. Calcif Tissue Int 103, 443–454 (2018). https://doi.org/10.1007/s00223-018-0439-8

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