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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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References

  1. Baxter NN, Habermann EB, Tepper JE, Durham SB, Virnig BA (2005) Risk of pelvic fractures in older women following pelvic irradiation. JAMA 294:2587–2593

    Article  CAS  PubMed  Google Scholar 

  2. Oh D, Huh SJ, Nam H, Park W, Han Y, do Lim H, Ahn YC, Lee JW, Kim BG, Bae DS, Lee JH (2008) Pelvic insufficiency fracture after pelvic radiotherapy for cervical cancer: analysis of risk factors. Int J Radiat Oncol Biol Phys 70:1183–1188

    Article  PubMed  Google Scholar 

  3. Voroney JP, Hope A, Dahele MR, Purdie TG, Franks KN, Pearson S, Cho JB, Sun A, Payne DG, Bissonnette JP, Bezjak A, Brade AM (2009) Chest wall pain and rib fracture after stereotactic radiotherapy for peripheral non-small cell lung cancer. J Thorac Oncol 4:1035–1037

    Article  PubMed  Google Scholar 

  4. Park SH, Kim JC, Lee JE, Park IK (2011) Pelvic insufficiency fracture after radiotherapy in patients with cervical cancer in the era of PET/CT. Radiat Oncol J 29:269–276

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dunlap NE, Cai J, Biedermann GB, Yang W, Benedict SH, Sheng K, Schefter TE, Kavanagh BD, Larner JM (2010) Chest wall volume receiving >30 Gy predicts risk of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 76:796–801

    Article  PubMed  Google Scholar 

  6. Helmstedter CS, Goebel M, Zlotecki R, Scarborough MT (2001) Pathologic fractures after surgery and radiation for soft tissue tumors. Clin Orthop Relat Res 389:165–172

    Article  PubMed  Google Scholar 

  7. Holt GE, Griffin AM, Pintilie M, Wunder JS, Catton C, O’Sullivan B, Bell RS (2005) Fractures following radiotherapy and limb-salvage surgery for lower extremity soft-tissue sarcomas. A comparison of high-dose and low-dose radiotherapy. J Bone Joint Surg Am 87:315–319

    Article  PubMed  Google Scholar 

  8. Bandstra ER, Pecaut MJ, Anderson ER, Willey JS, De Carlo F, Stock SR, Gridley DS, Nelson GA, Levine HG, Bateman TA (2008) Long-term dose response of trabecular bone in mice to proton radiation. Radiat Res 169:607–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hamilton SA, Pecaut MJ, Gridley DS, Travis ND, Bandstra ER, Willey JS, Nelson GA, Bateman TA (2006) A murine model for bone loss from therapeutic and space-relevant sources of radiation. J Appl Physiol 101:789–793

    Article  CAS  PubMed  Google Scholar 

  10. Willey JS, Livingston EW, Robbins ME, Bourland JD, Tirado-Lee L, Smith-Sielicki H, Bateman TA (2010) Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations. Bone 46:101–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Willey JS, Lloyd SA, Robbins ME, Bourland JD, Smith-Sielicki H, Bowman LC, Norrdin RW, Bateman TA (2008) Early increase in osteoclast number in mice after whole-body irradiation with 2 Gy X rays. Radiat Res 170:388–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Guise TA (2006) Bone loss and fracture risk associated with cancer therapy. Oncologist 11:1121–1131

    Article  CAS  PubMed  Google Scholar 

  13. Oest ME, Franken V, Kuchera T, Strauss J, Damron TA (2014) Long-term loss of osteoclasts and unopposed cortical mineral apposition following limited field irradiation. J Orthop Res 33:334–342

    Article  PubMed  PubMed Central  Google Scholar 

  14. Oteo-Alvaro A, Moreno E (2010) Atrophic humeral shaft nonunion treated with teriparatide (rh PTH 1-34): a case report. J Shoulder Elbow Surg 19:22–28

    Article  Google Scholar 

  15. Paridis D, Karachalios T (2011) Atrophic femoral bone nonunion treated with 1-84 PTH. J Musculoskelet Neuronal Interact 11:320–322 quiz 323

    CAS  PubMed  Google Scholar 

  16. Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA (2010) Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int 21:1041–1045

    Article  CAS  PubMed  Google Scholar 

  17. Gong B, Oest ME, Mann KA, Damron TA, Morris MD (2013) Raman spectroscopy demonstrates prolonged alteration of bone chemical composition following extremity localized irradiation. Bone 57:252–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oest ME, Damron TA (2014) Focal therapeutic irradiation induces an early transient increase in bone glycation. Radiat Res 181:439–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fowler JF (2010) 21 years of biologically effective dose. Br J Radiol 83:554–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hopewell JW (2003) Radiation-therapy effects on bone density. Med Pediatr Oncol 41:208–211

    Article  PubMed  Google Scholar 

  21. Doube M, Klosowski MM, Arganda-Carreras I, Cordelieres FP, Dougherty RP, Jackson JS, Schmid B, Hutchinson JR, Shefelbine SJ (2010) BoneJ: free and extensible bone image analysis in ImageJ. Bone 47:1076–1079

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wernle JD, Damron TA, Allen MJ, Mann KA (2010) Local irradiation alters bone morphology and increases bone fragility in a mouse model. J Biomech 43:2738–2746

    Article  PubMed  Google Scholar 

  23. van der Meulen MC, Jepsen KJ, Mikic B (2001) Understanding bone strength: size isn’t everything. Bone 29:101–104

    Article  PubMed  Google Scholar 

  24. Jepsen K (2011) Functional interactions among morphologic and tissue quality traits define bone quality. Clin Orthop Relat Res 469:2150–2159

    Article  PubMed  PubMed Central  Google Scholar 

  25. Li X, Qin L, Bergenstock M, Bevelock LM, Novack DV, Partridge NC (2007) Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. J Biol Chem 282:33098–33106

    Article  CAS  PubMed  Google Scholar 

  26. Whitfield JF (2005) Parathyroid hormone (PTH) and hematopoiesis: new support for some old observations. J Cell Biochem 96:278–284

    Article  CAS  PubMed  Google Scholar 

  27. Whitfield JF (2006) Parathyroid hormone: a novel tool for treating bone marrow depletion in cancer patients caused by chemotherapeutic drugs and ionizing radiation. Cancer Lett 244:8–15

    Article  CAS  PubMed  Google Scholar 

  28. Jacome-Galarza CE, Lee SK, Lorenzo JA, Aguila HL (2011) Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. J Bone Miner Res 26:1207–1216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jilka RL (2013) The relevance of mouse models for investigating age-related bone loss in humans. J Gerotol A Biol Sci Med Sci 68:1209–1217

    Article  Google Scholar 

  30. Arrington SA, Fisher ER, Willick GE, Mann KA, Allen MJ (2010) Anabolic and antiresorptive drugs improve trabecular microarchitecture and reduce fracture risk following radiation therapy. Calcif Tissue Int 87:263–272

    Article  CAS  PubMed  Google Scholar 

  31. Deshpande SS, Gallagher KK, Donneys A, Tchanque-Fossuo CN, Sarhaddi D, Nelson NS, Chepeha DB, Buchman SR (2013) Parathyroid hormone therapy mollifies radiation-induced biomechanical degradation in murine distraction osteogenesis. Plast Reconstr Surg 132:91e–100e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gallagher KK, Deshpande S, Tchanque-Fossuo CN, Donneys A, Sarhaddi D, Nelson NS, Chepeha DB, Buchman SR (2013) Role of parathyroid hormone therapy in reversing radiation-induced nonunion and normalization of radiomorphometrics in a murine mandibular model of distraction osteogenesis. Head Neck 35:1732–1737

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chandra A, Lan S, Zhu J, Lin T, Zhang X, Siclari VA, Altman AR, Cengel KA, Liu XS, Qin L (2013) PTH prevents the adverse effects of focal radiation on bone architecture in young rats. Bone 55:449–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chandra A, Lin T, Tribble MB, Zhu J, Altman AR, Tseng WJ, Zhang Y, Akintoye SO, Cengel K, Liu XS, Qin L (2014) PTH1-34 alleviates radiotherapy-induced local bone loss by improving osteoblast and osteocyte survival. Bone 67:33–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koh AJ, Novince CM, Li X, Wang T, Taichman RS, McCauley LK (2011) An irradiation-altered bone marrow microenvironment impacts anabolic actions of PTH. Endocrinology 152:4525–4536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Acil Y, Springer IN, Niehoff P, Gassling V, Warnke PH, Acmaz S, Sonmez TT, Kimmig B, Lefteris V, Wiltfang J (2007) Proof of direct radiogenic destruction of collagen in vitro. Strahlenther Onkol 183:374–379

    Article  PubMed  Google Scholar 

  37. Green DE, Adler BJ, Chan ME, Lennon JJ, Acerbo AS, Miller LM, Rubin CT (2013) Altered composition of bone as triggered by irradiation facilitates the rapid erosion of the matrix by both cellular and physicochemical processes. PLoS One 8:e64952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cao X, Wu X, Frassica D, Yu B, Pang L, Xian L, Wan M, Lei W, Armour M, Tryggestad E, Wong J, Wen CY, Lu WW, Frassica FJ (2011) Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells. Proc Natl Acad Sci USA 108:1609–1614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Green DE, Rubin CT (2014) Consequences of irradiation on bone and marrow phenotypes, and its relation to disruption of hematopoietic precursors. Bone 63C:87–94

    Article  Google Scholar 

  40. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ (2009) Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460:259–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–846

    Article  CAS  PubMed  Google Scholar 

  42. Calvi LM, Bromberg O, Rhee Y, Weber JM, Smith JN, Basil MJ, Frisch BJ, Bellido T (2012) Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells. Blood 119:2489–2499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Charles JF, Aliprantis AO (2014) Osteoclasts: more than ‘bone eaters’. Trends Mol Med 20:449–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Huber BC, Grabmaier U, Brunner S (2014) Impact of parathyroid hormone on bone marrow-derived stem cell mobilization and migration. World J Stem Cells 6:637–643

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lee SK, Lorenzo JA (1999) Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 140:3552–3561

    CAS  PubMed  Google Scholar 

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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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