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The effects of zoledronic acid treatment and endurance exercise on ovariectomy-induced osteopenia in Wistar rats

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Abstract

Background

This study investigated the effects of endurance exercise training and zoledronic acid (Zol) treatment on ovariectomy-induced osteopenia.

Methods

Middle-aged female Wistar rats were subjected to sham and ovariectomy surgeries and assigned to seven different groups according to Zol treatment doses and treadmill endurance exercise (Ex) training; these were the Sham, Ovx, Ovx + LowZ, Ovx + HighZ, Ovx + Ex, Ovx + LowZ + Ex, Ovx + HighZ + Ex groups. The subcutaneous doses for the low- and high-Zol-treated ovariectomized rats were 20 and 100 µg/kg, respectively. Total intervention period was 10 weeks.

Results

When comparing the Ovx groups to the Sham group, ovariectomy resulted in multiple compromises in bone histomorphometry, size-related measurements, and biomechanical properties. Two-way ANOVA was adopted to investigate the effects of Zol treatments and Ex on the six ovariectomized groups. In spongy bone histomorphometry, Zol treatment resulted in comprehensive preservation for all parameters, while exercise demonstrated benefits for osteoclastic number and mineralization activity. In serum marker assays, the Zol-treated rats had lower serum osteocalcin and IGF-1/IGFBP-3 molar ratio when compared to the non-treated rats. Exercise training significantly benefited metabolism through lower serum triglycerides, cholesterol, leptin, IGF-1 and IGF-1/IGFBP-3 molar ratio, along with increased IGFBP-3 and phosphorus (p < 0.05). In bone-size-related measurements and biomechanical property analyses, data were normalized to body weight. For whole bone strength, Zol treatments demonstrated higher bone fracture load (FL) and FL energy, while Ex showed benefits to yield load, FL, post-yield load energy, and stiffness. In tissue-level biomechanical properties, rats treated with the higher Zol dose were higher in yield stress and yield toughness. Exercise benefited most bone-size-related measurements, while the high Zol-treated rats showed smaller medullar area.

Conclusion

When combined with Zol treatments, exercise training did not demonstrate significant collaborative or modifying effects. Exercise and bisphosphonate tend to affect to bone through distinct pathways. A lower dose or different timing of Zol treatment or during a later phase of bisphosphonate treatment (drug holiday) might allow the occurrence of synergistic effects between Zol treatment and exercise.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

BMD:

Bone mineral density

BMC:

Bone mineral content

Zol:

Zoledronic acid

IGF-1:

Insulin-like growth factor-1

LI-IGF-1− / − :

Liver-specific IGF-1 inactivation

LowZ and HighZ:

Zol treatment dose at 20 and 100 µg/kg, respectively

EXE:

Endurance running training

MMA:

Methyl methacrylate

EDTA:

Ethylenediaminetetraacetic acid

BV/TV:

Bone volume ratio (%), Tb.Th.: trabecular thickness (μm)

Tb.Sp.:

Space between trabeculae (μm)

Tb.No.:

Trabeculae number (1/mm)

MS/BS:

Bone mineralization over bone surface (%)

TRAP:

Tartrate-resistant acid phosphatase

IGFBP-3:

Insulin-like growth factor binding protein-3

YL:

Yield load

FL:

Fracture load

FFDW:

Fat-free dry weight

Ct.Th.:

Cortical thickness (mm)

CS.Ar.:

Total cross-sectional area (mm2)

Ct.Ar.:

Cortical area (mm2)

Me.Ar.:

Medullar area (mm2)

CSMI:

Cross-sectional moment of inertia (mm4)

YS:

Yield stress

YT:

Yield toughness

EM:

Elastic modulus

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Acknowledgements

Jae Cody is deeply appreciated for her editorial assistance.

Funding

This study was supported by a grant from the National Science Council (NSC 97–2410-H-006–083-MY2, TAIWAN).

Author information

Author notes

  1. Hsin-Shih Lin and Rong-Sen Yang contributed equally to the present study.

Authors and Affiliations

  1. Institute of Physical Education, Health and Leisure Studies, National Cheng Kung University, Tainan, Taiwan

    Hsin-Shih Lin & Tsang-Hai Huang

  2. Department of Orthopaedics, National Taiwan University Hospital, Taipei, Taiwan

    Rong-Sen Yang

  3. Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, USA

    Jack L. Lewis

  4. Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan

    Ming-shi Chang

  5. Department of Physical Therapy, National Cheng Kung University, Tainan, Taiwan

    Ar-Tyan Hsu

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  1. Hsin-Shih Lin
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Contributions

HS. L and TH. H prepared figures, tables and conducted the whole animal experiment; JL. L provided the expertise in calculations of material properties; MS. C provided expertise in serum analyses; AT. H conducted the tissue biomechanical test; HS. L, RS. Y, and TH. H wrote the draft of manuscript. JL. L contributed to review and editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Tsang-Hai Huang.

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Conflict of interest

The authors declare that there is no conflict of interest.

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The procedures of animal experimentation throughout this study were approved by the Committee of Animal Study at National Cheng Kung University (Document Serial No. 97112).

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Lin, HS., Yang, RS., Lewis, J.L. et al. The effects of zoledronic acid treatment and endurance exercise on ovariectomy-induced osteopenia in Wistar rats. Sport Sci Health (2024). https://doi.org/10.1007/s11332-024-01181-0

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