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Effects of raloxifene and alendronate on non-enzymatic collagen cross-links and bone strength in ovariectomized rabbits in sequential treatments after daily human parathyroid hormone (1-34) administration

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Abstract

Summary

This study investigated the effects of raloxifene and alendronate to follow parathyroid hormone (PTH) on bone collagen and biomechanical properties in ovariectomized rabbits. Sequential treatments of raloxifene and alendronate after hPTH(1-34) treatment improved biomechanical properties with and without bone collagen improvement, respectively.

Introduction

The standard sequential treatment to follow human parathyroid hormone (hPTH) (1-34) therapy for osteoporosis has yet to be determined. The objective of this study was to compare the effects of raloxifene and alendronate treatments to follow daily hPTH(1-34) treatment on non-enzymatic collagen cross-links, bone mass, and bone strength in ovariectomized (OVX) rabbits.

Methods

From 3 months after ovariectomy, seven month-old female New Zealand white rabbits were given either vehicle or hPTH(1-34) (8 μg/kg/day), once daily for 5 months. After hPTH(1-34) treatment, the hPTH(1-34)-treated animals were divided into two groups, and given raloxifene (10 mg/kg, daily) orally or alendronate (100 μg/kg, twice weekly) subcutaneously for 5 months. We evaluated bone mineral density (BMD), bone structural parameters, advanced glycation end product (AGE) content in collagen, and bone mechanical parameters including intrinsic parameters in the femur.

Results

Raloxifene (hPTH/RLX) and alendronate (hPTH/ALN) to follow hPTH(1-34) increased cortical thickness, maximum load, and maximum stress and decreased endocortical surface in the diaphysis, in addition to increasing total BMD in the distal metaphysis. Decreased trabecular AGE, pentosidine, and homocysteine contents and increased toughness and breaking energy were noted with hPTH/RLX treatment only. With hPTH/ALN treatment, no effects on non-enzymatic collagen cross-link AGEs were noted although increases in stiffness and elastic modulus were observed.

Conclusion

These results suggest that sequential treatments with hPTH(1-34) and antiresorptive drugs (raloxifene and alendronate) have a beneficial effect on bone mass and biomechanical properties in OVX rabbits.

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Acknowledgments

The authors acknowledge Shin Nippon Biomedical Laboratories, Ltd., for the assistance with the preparation of the manuscript and Soshi Nagaoka (Eli Lilly Japan K.K.) for performing the statistical analysis.

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Authors and Affiliations

  1. Medical Science, Medicines Development Unit Japan, Eli Lilly Japan KK, Sannomiya Plaza Building 7-1-5 Isogami-dori, Chuo-ku, Kobe, 651-0086, Japan

    S. Kimura & Y. Isaka

  2. Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    M. Saito, Y. Kida & K. Marumo

  3. Hamri Co., Ltd., 2638-2, Osaki, Koga, Ibaraki, 306-0101, Japan

    A. Seki

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  1. S. Kimura
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Correspondence to S. Kimura.

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Funding

This study was funded by Eli Lilly Japan K.K.

Conflicts of interest

Shuichi Kimura and Yoshitaka Isaka are employees of Eli Lilly Japan K.K. Mitsuru Saito received research grants and/or consulting or speaking fees from Pfizer Inc., Eli Lilly, Chugai, Dai-ichi Sankyo, Asahikasei Pharma, Astellas Pharma, Taisho Toyama Pharma, Teijin Pharma, and Ono Pharma. Yoshikuni Kida, Azusa Seki, and Keishi Marumo declare that they have no conflict of interest.

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Kimura, S., Saito, M., Kida, Y. et al. Effects of raloxifene and alendronate on non-enzymatic collagen cross-links and bone strength in ovariectomized rabbits in sequential treatments after daily human parathyroid hormone (1-34) administration. Osteoporos Int 28, 1109–1119 (2017). https://doi.org/10.1007/s00198-016-3812-3

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