Ionizing Radiation and Bone Loss: Space Exploration and Clinical Therapy Applications

  • Jeffrey S. Willey
  • Shane A. J. Lloyd
  • Gregory A. Nelson
  • Ted A. BatemanEmail author
Original Paper


Damage to normal, nontumor bone tissue following therapeutic irradiation increases the risk of fracture among cancer patients. For example, women treated for various pelvic tumors have been shown to have a greater than 65% increased incidence of hip fracture by 5 years postradiotherapy. Another practical situation in which exposure to ionizing radiation may negatively impact skeletal integrity is during extended spaceflight missions. There is a limited understanding of how spaceflight-relevant doses and types of radiation can influence astronaut bone health, particularly when combined with the significant effects of mechanical unloading experienced in microgravity. Historically, negative effects on osteoblasts have been studied. Radiation exposure has been shown to damage osteoblast precursors. Damage to local vasculature has been observed, ranging from decreased lumen diameter to complete ablation within the irradiated volume, causing a state of hypoxia. These effects result in suppression of bone formation and a general state of low bone turnover. More recently, however, we have demonstrated in preclinical mouse models, a very rapid but transient increase in osteoclast activity after exposure to spaceflight and clinically relevant radiation doses. Combined with long-term suppression of bone formation, this skeletal damage may cause long-term deficits. This review will present a broad set of literature outlining our current set knowledge of both clinical therapy and space exploration exposure to ionizing radiation. Additionally, we will discuss prevention of the initial osteoclast-mediated bone loss, the need to promote normal bone turnover and long-term quality of bone tissue, and our hypothesized molecular mechanisms.


Osteoporosis Fracture Ionizing radiation Radiation therapy Spaceflight Microgravity Space radiation Osteoclasts Bone Inflammation 



This research is supported by the National Space Biomedical Research Institute through NASA NCC 9-58 (BL01302 TAB; PF01403 JSW), NASA Cooperative Agreements NCC9-79 and NCC9-149 (GAN), and the National Institutes of Health (NIAMS R21AR054889 TAB). Support was also provided by the National Institutes of Health (T32 CA113267 JSW). We want to thank Procter and Gamble Pharmaceuticals for providing an unrestricted grant (TAB JSW) and to the MD/PhD Program at The Pennsylvania State University College of Medicine for partial funding support (SAJL).


  1. 1.
    Kondo H, Searby ND, Mojarrab R, Phillips J, Alwood J, Yumoto K, Almeida EA, Limoli CL, Globus RK. Total-body irradiation of postpubertal mice with (137)Cs acutely compromises the microarchitecture of cancellous bone and increases osteoclasts. Radiat Res. 2009;171(3):283–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Willey JS, Livingston EW, Robbins ME, Bourland JD, Tirado-Lee L, Smith-Sielicki H, Bateman TA. Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations. Bone. 2010;46(1):101–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Spector ER, Smith SM, Sibonga JD. Skeletal effects of long-duration head-down bed rest. Aviat Space Environ Med. 2009;80(5 Suppl):A23–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A. Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. J Bone Miner Res. 2004;19(6):1006–12.PubMedCrossRefGoogle Scholar
  5. 5.
    Bikle DD, Halloran BP. The response of bone to unloading. J Bone Min Metab. 1999;17(4):233–44.CrossRefGoogle Scholar
  6. 6.
    Hamilton SA, Pecaut MJ, Gridley DS, Travis ND, Bandstra ER, Willey JS, Nelson GA, Bateman TA. A murine model for bone loss from therapeutic and space-relevant sources of radiation. J Appl Physiol. 2006;101(3):789–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Alwood JS, Yumoto K, Mojarrab R, Limoli CL, Almeida EA, Searby ND, Globus RK. Heavy ion irradiation and unloading effects on mouse lumbar vertebral microarchitecture, mechanical properties and tissue stresses. Bone. 2010;47(2):248–55.PubMedCrossRefGoogle Scholar
  8. 8.
    Kondo H, Yumoto K, Alwood JS, Mojarrab R, Wang A, Almeida EA, Searby ND, Limoli CL, Globus RK. Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse. J Appl Physiol. 2010;108(1):152–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Bandstra ER, Thompson RW, Nelson GA, Willey JS, Judex S, Cairns MA, Benton ER, Vazquez ME, Carson JA, Bateman TA. Musculoskeletal changes in mice from 20–50 cGy of simulated galactic cosmic rays. Radiat Res. 2009;172(1):21–9.PubMedCrossRefGoogle Scholar
  10. 10.
    NCRP. Report No. 132—radiation protection guidance for activities in low-earth orbit, in 2000. National Council on Radiation Protection and Measurements Bethesda, MD; 2000.Google Scholar
  11. 11.
    Baxter NN, Habermann EB, Tepper JE, Durham SB, Virnig BA. Risk of pelvic fractures in older women following pelvic irradiation. JAMA. 2005;294(20):2587–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Brown SA, Guise TA. Cancer treatment-related bone disease. Crit Rev Eukaryot Gene Expr. 2009;19(1):47–60.PubMedGoogle Scholar
  13. 13.
    Guise TA. Bone loss and fracture risk associated with cancer therapy. Oncologist. 2006;11(10):1121–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Florin TA, Fryer GE, Miyoshi T, Weitzman M, Mertens AC, Hudson MM, Sklar CA, Emmons K, Hinkle A, Whitton J, Stovall M, Robison LL, Oeffinger KC. Physical inactivity in adult survivors of childhood acute lymphoblastic leukemia: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2007;16(7):1356–63.PubMedCrossRefGoogle Scholar
  15. 15.
    Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Pierce SM, Recht A, Lingos TI, Abner A, Vicini F, Silver B, Herzog A, Harris JR. Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys. 1992;23(5):915–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Overgaard M. Spontaneous radiation-induced rib fractures in breast cancer patients treated with postmastectomy irradiation. A clinical radiobiological analysis of the influence of fraction size and dose-response relationships on late bone damage. Acta Oncol. 1988;27(2):117–22.PubMedCrossRefGoogle Scholar
  18. 18.
    Mitchell MJ, Logan PM. Radiation-induced changes in bone. Radiographics. 1998;18(5):1125–36. quiz 1242-3.PubMedGoogle Scholar
  19. 19.
    Williams HJ, Davies AM. The effect of X-rays on bone: a pictorial review. Eur Radiol. 2006;16(3):619–33.PubMedCrossRefGoogle Scholar
  20. 20.
    Howland W, Loeffler RK, Starchman DE, et al. Post-irradiation atrophic changes of bone and related complications. Radiology. 1975;117:677–85.PubMedGoogle Scholar
  21. 21.
    Ergun H, Howland WJ. Postradiation atrophy of mature bone. CRC Crit Rev Diagn Imaging. 1980;12(3):225–43.PubMedGoogle Scholar
  22. 22.
    Hopewell JW. Radiation-therapy effects on bone density. Med Pediatr Oncol. 2003;41(3):208–11.PubMedCrossRefGoogle Scholar
  23. 23.
    Furstman LL. Effect of radiation on bone. J Dent Res. 1972;51(2):596–604.PubMedCrossRefGoogle Scholar
  24. 24.
    Sawajiri M, Mizoe J. Changes in bone volume after irradiation with carbon ions. Radiat Environ Biophys. 2003;42(2):101–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Nishiyama K, Inaba F, Higashihara T, Kitatani K, Kozuka T. Radiation osteoporosis—an assessment using single energy quantitative computed tomography. Eur Radiol. 1992;2(4):322–5.CrossRefGoogle Scholar
  26. 26.
    Bandstra ER, Pecaut MJ, Anderson ER, Willey JS, De Carlo F, Stock SR, Gridley DS, Nelson GA, Levine HG, Bateman TA. Long-term dose response of trabecular bone in mice to proton radiation. Radiat Res. 2008;169(6):607–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Yumoto K, Globus RK, Mojarrab R, Arakaki J, Wang A, Searby ND, Almeida EA, Limoli CL. Short-term effects of whole-body exposure to (56)fe ions in combination with musculoskeletal disuse on bone cells. Radiat Res. 2010;173(4):494–504.PubMedCrossRefGoogle Scholar
  28. 28.
    Wernle JD, Damron TA, Allen MJ, Mann KA. Local irradiation alters bone morphology and increases bone fragility in a mouse model. J Biomech. 2010;43(14):2738–46.PubMedCrossRefGoogle Scholar
  29. 29.
    Sugimoto M, Takahashi S, Toguchida J, Kotoura Y, Shibamoto Y, Yamamuro T. Changes in bone after high-dose irradiation. Biomechanics and histomorphology. J Bone Joint Surg Br. 1991;73(3):492–7.PubMedGoogle Scholar
  30. 30.
    Nyaruba MM, Yamamoto I, Kimura H, Morita R. Bone fragility induced by X-ray irradiation in relation to cortical bone-mineral content. Acta Radiol. 1998;39(1):43–6.PubMedGoogle Scholar
  31. 31.
    Maeda M, Bryant MH, Yamagata M, Li G, Earle JD, Chao EY. Effects of irradiation on cortical bone and their time-related changes. A biomechanical and histomorphological study. J Bone Joint Surg Am. 1988;70(3):392–9.PubMedGoogle Scholar
  32. 32.
    Rohrer MD, Kim Y, Fayos JV. The effect of cobalt-60 irradiation on monkey mandibles. Oral Surg Oral Med Oral Pathol. 1979;48(5):424–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Margulies B, Morgan H, Allen M, Strauss J, Spadaro J, Damron T. Transiently increased bone density after irradiation and the radioprotectant drug amifostine in a rat model. Am J Clin Oncol. 2003;26(4):e106–14.PubMedGoogle Scholar
  34. 34.
    Bliss P, Parsons CA, Blake PR. Incidence and possible aetiological factors in the development of pelvic insufficiency fractures following radical radiotherapy. Br J Radiol. 1996;69(822):548–54.PubMedCrossRefGoogle Scholar
  35. 35.
    Konski A, Sowers M. Pelvic fractures following irradiation for endometrial carcinoma. Int J Radiat Oncol Biol Phys. 1996;35(2):361–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Gal TJ, Munoz-Antonia T, Muro-Cacho CA, Klotch DW. Radiation effects on osteoblasts in vitro: a potential role in osteoradionecrosis. Arch Otolaryngol Head Neck Surg. 2000;126(9):1124–8.PubMedGoogle Scholar
  37. 37.
    Ewing J. Radiation osteitis. Acta Radiol. 1926;6:399–412.CrossRefGoogle Scholar
  38. 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. Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells. Proc Natl Acad Sci U S A. 2011;108(4):1609–14.PubMedCrossRefGoogle Scholar
  39. 39.
    Sams A. The effect of 2000 r of x-rays on the internal structure of the mouse tibia. Int J Radiat Biol Relat Stud Phys Chem Med. 1966;11(1):51–68.PubMedCrossRefGoogle Scholar
  40. 40.
    Dudziak ME, Saadeh PB, Mehrara BJ, Steinbrech DS, Greenwald JA, Gittes GK, Longaker MT. The effects of ionizing radiation on osteoblast-like cells in vitro. Plast Reconstr Surg. 2000;106(5):1049–61.PubMedCrossRefGoogle Scholar
  41. 41.
    Szymczyk KH, Shapiro IM, Adams CS. Ionizing radiation sensitizes bone cells to apoptosis. Bone. 2004;34(1):148–56.PubMedCrossRefGoogle Scholar
  42. 42.
    Sakurai T, Sawada Y, Yoshimoto M, Kawai M, Miyakoshi J. Radiation-induced reduction of osteoblast differentiation in C2C12 cells. J Radiat Res (Tokyo). 2007;48(6):515–21.CrossRefGoogle Scholar
  43. 43.
    Sawajiri M, Nomura Y, Bhawal UK, Nishikiori R, Okazaki M, Mizoe J, Tanimoto K. Different effects of carbon ion and gamma-irradiation on expression of receptor activator of NF-kB ligand in MC3T3-E1 osteoblast cells. Bull Exp Biol Med. 2006;142(5):618–24.PubMedCrossRefGoogle Scholar
  44. 44.
    Schonmeyr BH, Wong AK, Soares M, Fernandez J, Clavin N, Mehrara BJ. Ionizing radiation of mesenchymal stem cells results in diminution of the precursor pool and limits potential for multilineage differentiation. Plast Reconstr Surg. 2008;122(1):64–76.PubMedCrossRefGoogle Scholar
  45. 45.
    Jacobsson M, Jonsson A, Albrektsson T, Turesson I. Alterations in bone regenerative capacity after low level gamma irradiation. Scand J Plastic Reconstr Surg. 1985;19:231–6.CrossRefGoogle Scholar
  46. 46.
    Rabelo GD, Beletti ME, Dechichi P. Histological analysis of the alterations on cortical bone channels network after radiotherapy: a rabbit study. Microsc Res Tech. 2010;73(11):1015–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Willey JS, Lloyd SA, Robbins ME, Bourland JD, Smith-Sielicki H, Bowman LC, Norrdin RW, Bateman TA. Early increase in osteoclast number in mice after whole-body irradiation with 2 Gy X rays. Radiat Res. 2008;170(3):388–92.PubMedCrossRefGoogle Scholar
  48. 48.
    Sawajiri M, Mizoe J, Tanimoto K. Changes in osteoclasts after irradiation with carbon ion particles. Radiat Environ Biophys. 2003;42(3):219–23.PubMedCrossRefGoogle Scholar
  49. 49.
    Burr DB, Miller L, Grynpas M, Li J, Boyde A, Mashiba T, Hirano T, Johnston CC. Tissue mineralization is increased following 1-year treatment with high doses of bisphosphonates in dogs. Bone. 2003;33(6):960–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Lorimore SA, Coates PJ, Scobie GE, Milne G, Wright EG. Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? Oncogene. 2001;20(48):7085–95.PubMedCrossRefGoogle Scholar
  51. 51.
    Robbins ME, Jaenke RS, Bywaters T, Golding SJ, Rezvani M, Whitehouse E, Hopewell JW. Sequential evaluation of radiation-induced glomerular ultrastructural changes in the pig kidney. Radiat Res. 1993;135(3):351–64.PubMedCrossRefGoogle Scholar
  52. 52.
    Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995;33(1):99–109.PubMedCrossRefGoogle Scholar
  53. 53.
    Van der Meeren A, Vandamme M, Squiban C, Gaugler MH, Mouthon MA. Inflammatory reaction and changes in expression of coagulation proteins on lung endothelial cells after total-body irradiation in mice. Radiat Res. 2003;160(6):637–46.PubMedCrossRefGoogle Scholar
  54. 54.
    Hosoi Y, Miyachi H, Matsumoto Y, Enomoto A, Nakagawa K, Suzuki N, Ono T. Induction of interleukin-1beta and interleukin-6 mRNA by low doses of ionizing radiation in macrophages. Int J Cancer. 2001;96(5):270–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Akmansu M, Unsal D, Bora H, Elbeg S. Influence of locoregional radiation treatment on tumor necrosis factor-alpha and interleukin-6 in the serum of patients with head and neck cancer. Cytokine. 2005;31(1):41–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Barcellos-Hoff MH. How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res. 1998;150(5 Suppl):S109–20.PubMedCrossRefGoogle Scholar
  57. 57.
    Bentzen SM. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat Rev Cancer. 2006;6(9):702–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Vujaskovic Z, Anscher MS, Feng QF, Rabbani ZN, Amin K, Samulski TS, Dewhirst MW, Haroon ZA. Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys. 2001;50(4):851–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Walsh MC, Choi Y. Biology of the TRANCE axis. Cytokine Growth Factor Rev. 2003;14(3–4):251–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Walsh NC, Crotti TN, Goldring SR, Gravallese EM. Rheumatic diseases: the effects of inflammation on bone. Immunol Rev. 2005;208:228–51.PubMedCrossRefGoogle Scholar
  61. 61.
    Smith MR, Lee WC, Brandman J, Wang Q, Botteman M, Pashos CL. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol. 2005;23(31):7897–903.PubMedCrossRefGoogle Scholar
  62. 62.
    Weitzmann MN, Pacifici R. The role of T lymphocytes in bone metabolism. Immunol Rev. 2005;208:154–68.PubMedCrossRefGoogle Scholar
  63. 63.
    Kimble RB, Srivastava S, Ross FP, Matayoshi A, Pacifici R. Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1 and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production. J Biol Chem. 1996;271(46):28890–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jeffrey S. Willey
    • 1
  • Shane A. J. Lloyd
    • 2
  • Gregory A. Nelson
    • 3
  • Ted A. Bateman
    • 4
    Email author
  1. 1.Section of Molecular Medicine and Department of Radiation Oncology, Comprehensive Cancer CenterWake Forest School of MedicineWinston-SalemUSA
  2. 2.Department of Orthopaedics and Rehabilitation, Division of Musculoskeletal SciencesThe Pennsylvania State University College of MedicineHersheyUSA
  3. 3.Department of Radiation MedicineLoma Linda UniversityLoma LindaUSA
  4. 4.Departments of Biomedical Engineering and Radiation OncologyUniversity of North CarolinaChapel HillUSA

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