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Parathyroid Hormone (1–34) Transiently Protects Against Radiation-Induced Bone Fragility

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Abstract

Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1–34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility.

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Acknowledgments

This study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health under award number AR065419, and by the David G. Murray Endowment (SUNY Upstate Medical University). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author Contributions

MEO was responsible for study design, execution, data analysis, and manuscript preparation. KAM contributed to study design, mechanical testing methods, statistical analysis, and manuscript preparation. NDZ contributed to study execution, data collection, and manuscript editing. TAD contributed the overall study concept, advised on study design and data interpretation, and assisted with manuscript preparation. All authors have read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA

    Megan E. Oest, Kenneth A. Mann, Nicholas D. Zimmerman & Timothy A. Damron

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  1. Megan E. Oest
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Correspondence to Megan E. Oest.

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The authors have no financial or professional conflicts of interest to disclose.

Human and Animal Rights and Informed Consent

All animal procedures were approved by, and performed in accordance with the ethical standards of, the SUNY Upstate Medical University Institutional Animal Care and Use Committee.

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Supplementary Table 1

Micro-CT results for the femoral cortical bone at mid-diaphysis. All values are reported as the average ± standard deviation. Supplementary material 1 (DOCX 91 kb)

Supplementary Table 2

Micro-CT results for the metaphyseal trabecular compartment of the femurs. All values are reported as the average ± standard deviation. Supplementary material 2 (DOCX 124 kb)

Supplementary Table 3

Micro-CT results for the distal 5mm of the femurs, and data from mechanical testing in axial compression. All values are reported as the average ± standard deviation. Supplementary material 3 (DOCX 102 kb)

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Oest, M.E., Mann, K.A., Zimmerman, N.D. et al. Parathyroid Hormone (1–34) Transiently Protects Against Radiation-Induced Bone Fragility. Calcif Tissue Int 98, 619–630 (2016). https://doi.org/10.1007/s00223-016-0111-0

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