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The effects of bazedoxifene in the ovariectomized aged cynomolgus monkey

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Abstract

Bazedoxifene (BZA) is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. This preclinical study evaluated the efficacy and safety of BZA in preventing ovariectomy (OVX)-induced bone loss in aged cynomolgus monkeys. Animals (18 per group) underwent OVX and were administered BZA (0.2, 0.5, 1, 5, or 25 mg/kg/day) or vehicle, or were sham-operated and administered vehicle, by daily oral gavage for 18 months. Biochemical markers of bone turnover were assessed at 6, 12, and 18 months, along with bone densitometry using dual energy X-ray absorptiometry and peripheral quantitative computed tomography. Animals were killed after 18 months. Uterine and pituitary weights were determined, and histomorphometric and biomechanical measurements were performed. OVX vehicle controls showed increases in bone turnover associated with cancellous and cortical bone osteopenia (in vivo), and slight decreases (not statistically significant) in biomechanical strength parameters at the lumbar spine and femoral neck. BZA partially preserved cortical and cancellous bone mass by preventing the OVX-induced increases in bone turnover. Although the response was often similar among BZA-treated groups, the strongest efficacy was generally seen at 25 mg/kg/day. Treatment with BZA did not adversely affect measures of bone strength and was well tolerated; there was no evidence of uterotrophic activity, mammary tissue was unaffected, and there were no adverse effects on plasma lipids. Treatment of ovariectomized animals with BZA partially prevented changes in bone remodeling that correlated with increases in bone mineral density, while maintaining bone strength and a favorable safety profile.

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Acknowledgments

This study was sponsored by Wyeth Research, which was acquired by Pfizer Inc in October 2009. We are grateful to the excellent technical expertise of the Imaging, Histomorphometry, and Biomechanics teams at Charles River Laboratories, who were paid contractors to Wyeth in connection with study execution. Medical writing support for this manuscript was provided by Katie Gersh, PhD, of MedErgy and Linda Romagnano, PhD, of Peloton Advantage and was funded by Pfizer.

Conflict of interest

B. Komm is an employee of Pfizer Inc (previously Wyeth Research), Collegeville, PA, USA. All other authors are employees of Charles River Laboratories who were paid contractors to Wyeth in connection with study execution. They report no other relevant conflicts of interest.

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Authors and Affiliations

  1. Charles River Preclinical Services, 22022 Transcanadienne, Senneville, QC, H9X 3R3, Canada

    Susan Y. Smith, Jacquelin Jolette & Luc Chouinard

  2. Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA

    Barry S. Komm

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  1. Susan Y. Smith
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  2. Jacquelin Jolette
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  3. Luc Chouinard
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  4. Barry S. Komm
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Correspondence to Barry S. Komm.

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Smith, S.Y., Jolette, J., Chouinard, L. et al. The effects of bazedoxifene in the ovariectomized aged cynomolgus monkey. J Bone Miner Metab 33, 161–172 (2015). https://doi.org/10.1007/s00774-014-0580-z

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  • DOI: https://doi.org/10.1007/s00774-014-0580-z

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