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Effects of Selective Androgen Receptor Modulator (SARM) Treatment in Osteopenic Female Rats

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Abstract

Purpose

Although androgens are known to protect bone, side effects and poor oral bioavailability have limited their use. We previously reported that S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (S-4) is a potent and tissue-selective androgen receptor modulator (SARM). This study was designed to evaluate the skeletal effects of S-4 in an osteopenic model.

Methods

Aged female rats were gonadectomized or sham operated on day 1 and assigned to treatment groups. Dosing was initiated on day 90 and continued daily until day 210. Whole animal bone mineral density (BMD), body weight, and fat mass were determined by dual energy x-ray absorptiometry (DEXA). Regional analysis of excised bones was performed using DEXA or computed tomography. Femur strength was evaluated by 3-point bending.

Results

S-4 restored whole body and lumbar vertebrae (L5-L6) BMD to the level of intact controls. Significant increases in cortical bone quality were observed at the femoral midshaft, resulting in increased load bearing capacity.

Conclusions

S-4 demonstrated partial/complete recovery of bone parameters to age-matched intact levels. Increased efficacy observed in cortical bone sites is consistent with reported androgen action in bone. The ability of S-4 to promote bone anabolism, prevent bone resorption, and increase skeletal muscle mass/strength positions these drugs as promising new alternatives for the treatment of osteoporosis.

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ACKNOWLEDGEMENT

The authors would like to thank Dr. Juhyun Kim, Dr. Jun Yang, Dr. Victor Shen, and Dr. Mitch Steiner for their technical assistance and advice.

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Authors and Affiliations

  1. College of Pharmacy, Division of Pharmaceutics, The Ohio State University, Columbus, Ohio, 43210, USA

    Jeffrey D. Kearbey, Wenqing Gao, Scott J. Fisher, Di Wu & James T. Dalton

  2. GTx, Inc., 3 N. Dunlap St., Memphis, Tennessee, 38163, USA

    Jeffrey D. Kearbey, Duane D. Miller & James T. Dalton

  3. Graduate Health Sciences Center, College of Pharmacy, Department of Pharmaceutical Sciences, University of Tennessee, Memphis, Tennessee, 38163, USA

    Duane D. Miller

Authors
  1. Jeffrey D. Kearbey
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  2. Wenqing Gao
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  3. Scott J. Fisher
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  4. Di Wu
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  5. Duane D. Miller
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  6. James T. Dalton
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Corresponding author

Correspondence to James T. Dalton.

Additional information

Funding Sources Supported by a grant from GTx, Inc., Memphis, TN.

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Kearbey, J.D., Gao, W., Fisher, S.J. et al. Effects of Selective Androgen Receptor Modulator (SARM) Treatment in Osteopenic Female Rats. Pharm Res 26, 2471–2477 (2009). https://doi.org/10.1007/s11095-009-9962-7

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  • DOI: https://doi.org/10.1007/s11095-009-9962-7

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