J Appl Physiol 101: 789-793, 2006.
First published June 1, 2006; doi:10.1152/japplphysiol.01078.2005
8750-7587/06 $8.00
A murine model for bone loss from therapeutic and space-relevant sources of radiation
S. A. Hamilton,1
M. J. Pecaut,2
D. S. Gridley,2
N. D. Travis,1
E. R. Bandstra,1
J. S. Willey,1
G. A. Nelson,2 and
T. A. Bateman1
1Department of Bioengineering, Clemson University, Clemson, South Carolina; and 2Department of Radiaiton Medicine, Loma Linda University and Medical Center, Loma Linda, California
Submitted 6 September 2005
; accepted in final form 19 May 2006
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ABSTRACT
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Cancer patients receiving radiation therapy are exposed to photon (gamma/X-ray), electron, and less commonly proton radiation. Similarly, astronauts on exploratory missions will be exposed to extended periods of lower-dose radiation from multiple sources and of multiple types, including heavy ions. Therapeutic doses of radiation have been shown to have deleterious consequences on bone health, occasionally causing osteoradionecrosis and spontaneous fractures. However, no animal model exists to study the cause of radiation-induced osteoporosis. Additionally, the effect of lower doses of ionizing radiation, including heavy ions, on general bone quality has not been investigated. This study presents data developing a murine model for radiation-induced bone loss. Female C57BL/6 mice were exposed to gamma, proton, carbon, or iron radiation at 2-Gray doses, representing both a clinical treatment fraction and spaceflight exposure for an exploratory mission. Mice were euthanized 110 days after irradiation. The proximal tibiae and femur diaphyses were analyzed using microcomputed tomography. Results demonstrate profound changes in trabecular architecture. Significant losses in trabecular bone volume fraction were observed for all radiation species: gamma, (–29%), proton (–35%), carbon (–39%), and iron (–34%). Trabecular connectivity density, thickness, spacing, and number were also affected. These data have clear implications for clinical radiotherapy in that bone loss in an animal model has been demonstrated at low doses. Additionally, these data suggest that space radiation has the potential to exacerbate the bone loss caused by microgravity, although lower doses and dose rates need to be studied.
heavy ion; microcomputed tomography; osteoporosis; microarchitecture; cancer
EXPOSURE TO IONIZING RADIATION for cancer therapy or during long-duration spaceflight has known deleterious effects (6, 13, 32, 33). Therapeutic radiation, an important tool in cancer treatment, involves exposure to photon (gamma/X-ray), electron, and less commonly proton radiation. Damage to normal tissue outside the treatment volume is an unavoidable consequence of radiation therapy and sets practical limits to treatment plans (30). Similarly, astronauts on exploratory missions beyond low-Earth orbit will be exposed to high-energy heavy ions in addition to proton and photon radiation, although for protracted periods and at lower doses and dose rates compared with therapy. The effect of ionizing radiation on the skeletal system has not been examined in detail. We propose that exposure to ionizing radiations of different qualities [gamma, proton, carbon, or iron at 2-Gray (Gy) dose levels; Gy = J/kg] has negative effects on bone microarchitecture in both cancer patients and in astronauts.
Clinical application.
Skeletal complications from radiation therapy have been described for breast, brain, and pelvic cancers and leukemia (bone-marrow transplants) (1, 3, 9, 21). These problems include reduced bone density (18), fractures (3), osteoradionecrosis (11), and back pain (36) affecting both children and adults (3, 18, 35). Improved survivorship rates of cancer patients receiving radiotherapy (28) increase the importance of understanding the mechanisms and long-term effects of radiation-induced bone loss.
Radiation therapy is administered to the whole body (preceding bone marrow transplant) or locally, targeting the tumor. Protocols vary considerably, but generally whole body irradiation totals 10–15 Gy and is administered in daily fractions of 1–2 Gy, whereas local therapy totals 40–70 Gy delivered in 
2-Gy fractions (17).
A recent retrospective analysis of more than 6,000 postmenopausal women receiving radiotherapy for cervical, rectal, and anal cancers established a significant correlation between radiation therapy and increased fracture risk (3). Risk of hip fracture among these patients was significantly elevated 5 yr posttherapy (relative risks of 1.66, 1.65, and 3.16, respectively). Understanding the role of radiation therapy in fracture risk is complicated by the fact that this bone loss is often accompanied by several contributors to low bone density, including premature menopause, androgen deficiency, and/or chemotherapy and the direct effect of cancer on bone loss (4, 27, 30). Identifying the independent effects of radiation on the skeletal system requires an animal model. To date, one does not exist.
Spaceflight application.
Prolonged exposure to microgravity has negative effects on the skeletal system (20). Recent examination of astronauts on the International Space Station reported 0.8–1.5% bone loss per month in the vertebrae and femoral neck, with site-specific losses exceeding 2% per month (20) and an incomplete recovery 5 yr after returning to Earth (31). During exploratory missions, astronauts will face both microgravity and radiation from cosmic and solar sources. The nature of space radiation is complex, with components ranging from protons to iron particles, accompanied by secondary radiation (e.g., Bremmstrahlung X-rays and neutrons) produced as heavy ions generate fragments when they strike shielding materials and the Martian atmosphere (7, 12, 29). It is unclear how bone, already compromised by microgravity or partial gravity, will be affected by exposure to space radiation.
NASA's current exploration roadmap outlines a return to the moon before voyages to Mars. During lunar missions, unexpected solar particle events (SPEs), such as solar flares and coronal mass ejections, are of primary concern. Although shielding can largely mitigate proton exposure from SPEs, the warning provided by surveillance may not permit complete protection during extra-vehicular activities: astronauts may have as few as 18 min from visual observation of the X-ray signature from an SPE to the initial upsurge of proton fluence (29). Even with shielding, infrequent, large SPEs, such as those observed during August 1972 and October 1989, can expose astronauts to considerable doses (25). Unprotected, astronauts could be exposed to potentially lethal doses. Even protected by 5 g/cm2 of mass (0.75 in. of aluminum or 2 in. of water), astronauts could receive whole body doses approaching 2 Gy (25). Considering the planned duration of the missions (6 mo) and the relative permanence compared with the Apollo program, it should be assumed that astronauts will eventually be exposed to these health-threatening doses.
Human exploration will eventually progress to Mars. Although SPEs will be a factor during these missions, concern about chronic exposure to cosmic rays will increase. During transit, astronauts will ideally have quick access to a "storm shelter," and while on the Martian surface the thin atmosphere, direct shielding from soil (2), and increased distance from the sun will all provide additional protection from protons. The duration of this mission, expected to be 30–36 mo, will result in accumulation of doses from heavy ions (29). Although the fluence (number of particles) of heavy ions is much less than that of protons, energy deposition from individual particles is much greater (29). Because neither conventional shielding nor the Martian atmosphere will effectively protect astronauts from cosmic radiation, in addition to heavy ions, they will also be exposed to a complex mix of secondary particle radiation composed primarily of protons, helium nuclei (high-velocity alpha particles), and highly penetrating neutrons (34).
Many variables will affect the exposures received in space, including the amount and composition of shielding material, duration in transit and on the Martian surface, and the level of solar activity during the mission; SPEs effectively reduce the fluence of heavy ion radiation (29). However, based on measured dose rates on the Space Shuttle, Skylab, and Apollo missions, a range of 0.5 to 1.0 Gy is appropriate for planning purposes (8, 22). An animal model is necessary to identify the radiation-specific effects on the skeletal system, to determine mechanisms, and to develop and test countermeasures.
Murine model.
This paper presents the initial development of an animal model to study the effect of clinically and space exploration-relevant components of radiation on the skeletal system. Using microcomputed tomography, we characterized the effects of single-dose, whole body (2 Gy) exposure to gamma, proton, carbon, or iron radiation on the skeletal system of female mice.
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MATERIALS AND METHODS
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Animals.
Nine-week-old, female C57BL/6 mice (n = 48; Charles River Laboratories, Wilmington, MA) were acclimatized for 1 wk before irradiation. Food and water were available ad libitum. The Institutional Animal Care and Use Committees of both Loma Linda University Medical Center and Brookhaven National Laboratory approved all procedures.
Radiation.
Four groups of mice received whole body irradiation using 60-Cobalt (60Co) gamma rays, linear energy transfer (LET) = 0.23 keV/µm, n = 10; protons (1H1+, 250 MeV/n), LET = 0.4 keV/µm, n = 10; carbon (12C6+, 290 MeV/n), LET = 13 keV/µm, n = 9; or iron (56Fe26+, 1 GeV/n), LET = 148 keV/µm, n = 9. A control group (n = 10) was not irradiated. Low-LET exposures (60Co and protons) were performed at Loma Linda University Medical Center as previously described (14, 15). For 60Co irradiation, a horizontal beam from a retired AECL (Atomic Energy of Canada; Commercial Products Division, Ottawa, Canada) Eldorado therapy unit was used. Protons were delivered in 0.3-s pulses every 2.2 s. High-LET exposures (C and Fe) were performed at the Brookhaven National Laboratory in the NASA Space Radiation Laboratory according to standardized procedures. Before radiation, the animals were placed individually into rectangular polystyrene boxes with air holes (30x 30x 85 mm) as previously described (14). All irradiations were delivered as 25–40 pulses/min to yield a cumulative 2 Gy with average dose rates ranging from 0.6 to 1.2 Gy/min. Particle radiation (protons, carbon, and iron) was delivered at the entrance plateau region of the beam, at the beginning of the Bragg Peak, such that LET levels were held constant throughout the target volume. Four to eight unanesthetized mice were irradiated simultaneously. The irradiation conditions were coordinated between investigators at the two facilities. Thus exposures were performed with uniform procedures and fixtures, and euthanasia and tissue harvesting occurred at a similar time postexposure. The mice irradiated at Brookhaven National Laboratory were shipped within days to Loma Linda University for housing and analysis. Animals were euthanized with 100% CO2 at 110 days postexposure as previously described (26).
Determination of microarchitecture.
The left tibiae and femurs were removed and cleaned of all nonosseous tissue and were allowed to air dry for 24 h. Bone sections of the proximal tibia were analyzed by microcomputed tomography (µCT20; Scanco Medical, Bassersdorf, Switzerland). The microcomputed tomography analysis was used to produce images for visual comparison and to determine microarchitectural parameters, including total volume, bone volume, cortical porosity, connectivity density, trabecular bone volume fraction, and trabecular spacing, thickness, and number. Bone structure and microarchitecture were imaged at a resolution of 15 µm (9-µm voxel size). Trabecular scans were performed starting just below the growth plate and extending distally 1 mm. To analyze cortical porosity and bone volume, femur length was measured and scans were performed at one-third of the length from the proximal end of the bone at the third trochanter.
Statistics.
Statistical analyses were performed using SAS software (SAS Institute, Cary, NC). Statistical comparisons were performed using one-way ANOVAs with a Tukey's test for follow-up comparisons. The level of significance (type I error) was set at 95%. Data are presented as means ±SE.
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RESULTS
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The trabecular bone volume fraction (Fig. 1) indicates significant declines in all radiation groups: gamma (–29%), proton (–35%), carbon (–39%), and iron (–34%). Proton-irradiated bones exhibited the largest decline in connectivity (–64%, Fig. 2), with all groups showing significant declines vs. control: gamma (–54%), carbon (–54%), and iron (–46%).
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Fig. 1. Trabecular bone volume fraction at the proximal tibiae. Loss of bone volume is a clear indication of osteopenia and results in inefficient load transmittal within trabecular bone. Values are means ± SE. *Significant differences from control (P < 0.05).
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Fig. 2. Connectivity densities of trabecular bone at the proximal tibiae. This degree of connectivity loss suggests that radiation-induced bone loss may be permanent. Further reduction in bone strength is possible because severed struts no longer transmit load. Values are means ± SE. *Significant differences from control (P < 0.05).
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Both low-LET-radiation groups showed an insignificant increase in trabecular thickness compared with control (Fig. 3): gamma (+5%) and proton (+6%). High-LET exposures resulted in significant declines vs. controls for trabecular thickness: carbon (–10%) and iron (–11%). This is the only demonstration of an LET/fluence effect. For trabecular number (Table 1), proton irradiation resulted in a significant decline (–20%) compared with control, with other radiation types causing insignificant declines: gamma (–16%), carbon (–14%), and iron (–10%). Trabecular separation or spacing (Table 1) was highest in the proton-irradiated group (+21%), with all other types also increasing (without significance) compared with control values: gamma (+19%), carbon (+13%), and iron (+8%). In the cortical scans, no significant differences in cortical porosity or cortical bone volume were observed (Table 1; see Fig. 4 for microcomputed tomography images).
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Fig. 3. Trabecular thickness at the proximal tibia. This is the only parameter where an LET effect was observed: the difference between low-LET radiation type (gamma and proton) and high-LET (carbon and iron) is highly significant (P < 0.01). Decline in trabecular thickness can result in a decrease in overall bone strength. Values are means ± SE. *Significant differences from control (P < 0.05).
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Fig. 4. Representative three-dimensional microcomputer tomography (CT) images of proximal tibiae for control, gamma-, proton-, carbon-, and iron-irradiated mice, respectively. The area shown is from below the growth plate extending distally 1 mm. Bar represents 1 mm.
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DISCUSSION
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This study reports profound declines in trabecular bone parameters 4 mo after exposure to 2-Gy doses of both clinically (gamma and proton) and space (proton, carbon and iron)-relevant sources of radiation. The 29–39% decline in trabecular volume fraction mirrors the reduced bone mineral density experienced by both postmenopausal women and astronauts, since the rate of bone loss is greatest in trabecular bone for both groups (10, 20). The 46–64% decline in trabecular connectivity suggests that this functional deficit may be permanent. The only difference between low-LET radiation (gamma and proton) and high-LET particles (carbon and iron) in our analysis was the effect on trabecular thickness (Fig. 3). Thus 2-Gy doses of radiation of diverse types result in similar functional losses of trabecular bone, regardless of the underlying physical and molecular mechanisms.
That microarchitecture is coupled to the mechanical properties of bone is well documented (5, 16). Several studies have suggested that trabecular number and integrity (connectivity) are important contributors to bone strength and mechanical competency (16, 24). Connectivity density sharply declined in the irradiated bones, and trabecular number showed significant declines in the proton group. Loss of trabecular connectivity results in loads no longer being transferred through a given strut. Once loading is eliminated in a trabecula, per Wolff's Law, trabecular bone density continues to decline (19, 23, 24). When a strut has lost the ability to transmit loads, connectivity cannot be repaired, and although bone mass may recover, efficiency in transmitting loads is reduced.
This long-term decline in trabecular competency could be caused either by a decrease in bone formation or by an increase in bone resorption. Clinically, whole body radiation (which kills stromal stem cells and thus chondrocyte and osteoblast precursors, affecting bone formation and growth) is used to eliminate native bone marrow when transplants are necessary (1). However, based on related studies in our laboratory, we believe that this net loss in bone mass is mediated by a long-term increase bone resorption (Willey JS, unpublished observations). In low bone mass conditions, such as those existing in microgravity and for postmenopausal osteoporosis, deficits in microarchitecture add to the risk of fracture (5). Therefore, radiation-induced bone loss may have a nonlinear effect on bone strength. Indeed, fracture risk has been shown to be elevated in postmenopausal women receiving pelvic radiotherapy (3). It should be noted that 2 Gy is a significantly lower dose than cancer patients receive during treatment (17), approximately equal to a single fraction.
The radiation astronauts will receive on exploratory missions to the moon and Mars is fundamentally different than regimes used for cancer therapy. Proton exposure during SPEs and the heavy ions in galactic cosmic rays are threats. SPEs will be a primary concern for astronauts on the lunar surface. A 2-Gy dose of proton radiation is possible, although it will be delivered over hours to days rather than in minutes, as administered for this study. A lower dose rate is generally believed to have a sparing effect, depending on the biomedical condition (7, 34). Because of the mission's greater duration, exposure to heavy ions from cosmic radiation is of primary concern on a trip to Mars. For a Mars mission, the composite dose of heavy ions will likely be 0.5–1.0 Gy, not the 2 Gy examined here (8, 22). The dose rate will also be much less, although for heavy ions cumulative dose appears to be more important than dose rate (29). Finally, on missions to both the moon and Mars, astronauts will be exposed to radiation of wide-ranging energies (traveling different velocities), whereas the types of radiation examined here were relatively monoenergetic.
The negative biological outcome of heavy-ion radiation is generally much greater than that of low-LET radiation. This is referred to as the relative biological effect (RBE). The same energy of carbon or iron radiation will usually produce a greater biological result in living systems than smaller charged particles or photons (32, 33). RBE for any particular charged particle depends on the biological model (i.e., in vitro vs. in vivo), the biomedical outcome (e.g., different cancers in different mouse strains), and tissue (e.g., lung vs. muscle) (7). The nature of space radiation, with its variable types, energies, and resulting secondary particle emissions, complicates estimation of the effective dose astronauts will receive. The word "uncertain" is disturbingly common in radiation biology reports. An enormous amount of research is required before astronauts can safely explore Mars.
Except for trabecular thickness, no differences were observed in this study between low-LET and high-LET radiation. No RBE for bone loss was observed at this dose. This is not entirely unexpected; there may be a differential response to low- and high-LET radiation at lower doses. RBE is generally nonlinear and calculated based on the linear portion of the response curve at low doses (<0.5 Gy) (17). Indeed, the physical mechanism of heavy-ion radiation and its interaction with the unique matrix of bone is different than that of photons and protons. Bone is a distinctive tissue: it is 70% more dense than other components of the body. This greater density is attributed to the mineral phase of bone, and particularly the Ca2+ (calcium) and P (phosphorous) constituents of hydroxyapatite. The existence of these relatively heavy elements in bone will cause fragmentation of high-LET radiation. The nuclei of elements with greater atomic number are more likely to collide and fragment, creating protons, neutrons, and alpha particles. The RBE of neutrons and alpha particles are of particular concern.
In conclusion, we have identified significant trabecular bone loss in mice irradiated with 2-Gy doses of gamma, proton, carbon, or iron radiation. This has implications for both radiotherapy patients and for astronauts on exploratory missions. To better understand the pathological causes for bone loss in either population, an animal model is necessary. Indeed, the many variables associated with clinical radiation, including chemotherapy, hormone changes, other medications, and the impact of cancer on bone, necessitates a model to identify the independent effects of radiation on bone (30). Further development of this model is necessary, including the characterization of the time course of the loss, the potential sparing effect of fractionation and low-dose rate, and identification of dose thresholds, so that molecular mechanisms and therapies can be examined.
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GRANTS
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Support for this work was funded by Procter and Gamble Pharmaceutics, the National Space Biomedical Research Institute through NASA NCC 9-58, BioServe Space Technologies (NASA NCC8-242), and a NASA GSRP Fellowship (NGT5-50440). The general irradiation procedures, collection of bone, and Loma Linda personnel were supported by NASA Cooperative Agreement (NCC9-79).
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DISCLOSURES
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The analysis of bone was primarily supported by an unrestricted grant from Procter and Gamble Pharmaceuticals.
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ACKNOWLEDGMENTS
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The authors thank Michael F. Moyers for 60Co and proton dose calibrations and Melba L. Andres, Anna L. Smith, and Steve Rightnar for expert technical assistance. Gratitude is also extended to Marcelo Vazquez, Peter Guida, Betsy Sutherland, Laura Thompson, Adele Billups, and the rest of the NASA Space Radiation Laboratory (NSRL) staff; Mary Ann Kershaw, Kerry Bonti, and other Brookhaven National Laboratory Animal Care Facility staff; and Adam Rusek and the physics support staff at Brookhaven National Laboratory NSRL. The editing and formatting assistance of Jenny Bourne is greatly appreciated.
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FOOTNOTES
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Address for reprint requests and other correspondence: T. A. Bateman, Dept. of Bioengineering, Clemson Univ., 501 Rhodes Research Center, Clemson, SC 29634 (e-mail: bateman{at}clemson.edu)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Copyright © 2006 by the American Physiological Society.
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ABSTRACT
MATERIALS AND METHODS
