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Differing Effects of Parathyroid Hormone, Alendronate, and Odanacatib on Bone Formation and on the Mineralization Process in Intracortical and Endocortical Bone of Ovariectomized Rabbits

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Abstract

Bone is formed by deposition of a collagen-containing matrix (osteoid) that hardens over time as mineral crystals accrue and are modified; this continues until bone remodeling renews that site. Pharmacological agents for osteoporosis differ in their effects on bone remodeling, and we hypothesized that they may differently modify bone mineral accrual. We, therefore, assessed newly formed bone in mature ovariectomized rabbits treated with the anti-resorptive bisphosphonate alendronate (ALN—100µ g/kg/2×/week), the anabolic parathyroid hormone (PTH (1–34)—15µ g/kg/5×/week), or the experimental anti-resorptive odanacatib (ODN 7.5 µM/day), which suppresses bone resorption without suppressing bone formation. Treatments were administered for 10 months commencing 6 months after ovariectomy (OVX). Strength testing, histomorphometry, and synchrotron Fourier-transform infrared microspectroscopy were used to measure bone strength, bone formation, and mineral accrual, respectively, in newly formed endocortical and intracortical bone. In Sham and OVX endocortical and intracortical bone, three modifications occurred as the bone matrix aged: mineral accrual (increase in mineral:matrix ratio), carbonate substitution (increase in carbonate:mineral ratio), and collagen molecular compaction (decrease in amide I:II ratio). ALN suppressed bone formation but mineral accrued normally at those sites where bone formation occurred. PTH stimulated bone formation on endocortical, periosteal, and intracortical bone surfaces, but mineral accrual and carbonate substitution were suppressed, particularly in intracortical bone. ODN treatment did not suppress bone formation, but newly deposited endocortical bone matured more slowly with ODN, and ODN-treated intracortical bone had less carbonate substitution than controls. In conclusion, these agents differ in their effects on the bone matrix. While ALN suppresses bone formation, it does not modify bone mineral accrual in endocortical or intracortical bone. While ODN does not suppress bone formation, it slows matrix maturation. PTH stimulates modelling-based bone formation not only on endocortical and trabecular surfaces, but may also do so in intracortical bone; at this site, new bone deposited contains less mineral than normal.

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Acknowledgements

The authors gratefully acknowledge technical assistance from Christine Jun, advice on the KKT method from Alvin Acerbo and Lisa Miller at Brookhaven National Laboratories, and very helpful critique from T. John Martin. This work was funded by an investigator-initiated Grant from MSD (AU) (No. 53291) to NAS. NAS was funded by an NHMRC Senior Research Fellowship. sFTIRM was undertaken on the Infrared Microspectroscopy beamline at the Australian Synchrotron, part of ANSTO. St. Vincent’s Institute receives funds from the Victorian Government’s Operational Infrastructure Support Program.

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Authors and Affiliations

  1. St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia

    Christina Vrahnas, Thomas A. Pearson & Natalie A. Sims

  2. Department of Medicine at St. Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, Australia

    Christina Vrahnas & Natalie A. Sims

  3. School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia

    Pascal R. Buenzli

  4. MRL, Merck & Co., Inc., West Point, PA, USA

    Brenda L. Pennypacker & Le T. Duong

  5. The Australian Synchrotron, Clayton, VIC, Australia

    Mark J. Tobin & Keith R. Bambery

  6. Australian Nuclear Science and Technology Organisation, The Australian Synchrotron, Lucas Heights, NSW, Australia

    Keith R. Bambery

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  1. Christina Vrahnas
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  4. Brenda L. Pennypacker
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Contributions

Study design: NAS and LTD. Study conduct: NAS, CV, PB, TAP, BLP, KRB. Data collection: CV, TAP, BLP. Data analysis: CV, TAP, BLP, NAS. Data interpretation: CV, PB, KRB, LTD, NAS. Drafting manuscript: CV, PB and NAS. Revising manuscript content: all authors. Approving final version of manuscript: All authors. NAS takes responsibility for the integrity of the data analysis.

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Correspondence to Natalie A. Sims.

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Conflict of interest

Brenda L. Pennypacker is, and Le T. Duong was, an employee of Merck & Co., Inc., Kenilworth, NJ, USA which partly sponsored the study through an investigator-initiated grant to NAS. Christina Vrahnas, Pascal R. Buenzli, Thomas A. Pearson, Keith R. Bambery and Mark J. Tobin declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This study was conducted in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of MRL, West Point. For this type of study formal consent is not required

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Vrahnas, C., Buenzli, P.R., Pearson, T.A. et al. Differing Effects of Parathyroid Hormone, Alendronate, and Odanacatib on Bone Formation and on the Mineralization Process in Intracortical and Endocortical Bone of Ovariectomized Rabbits. Calcif Tissue Int 103, 625–637 (2018). https://doi.org/10.1007/s00223-018-0455-8

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