Mechanical loading causes site-specific anabolic effects on bone following exposure to ionizing radiation

Shirazi‐Fard, Yasaman; Alwood, Joshua S.; Schreurs, Ann-Sofie; Castillo, Alesha B.; Globus, Ruth K.

doi:10.1016/j.bone.2015.07.019

Cited by 16 publications

(11 citation statements)

References 68 publications

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“…Intriguingly, Willie, et al [48] found that mice subjected to 4 microCT scans over the course of compression loading gained even greater Tb.BV/TV than mice scanned once. This result and long-term results from Shirazi-Fard, et al [17] agree with our finding that irradiated bone maintains the capacity to respond to mechanical loads.…”

Section: Discussionsupporting

confidence: 93%

“…In vivo compression loading of mouse tibias increases both trabecular and cortical bone mass [14–16]. Similarly, mouse tibias compression loaded 5 months after a localized, space travel-pertinent dose of 2 Gy heavy ion irradiation also demonstrated increased periosteal bone formation rates [17]. However, this irradiation had no observed effect on bone microstructure and transient changes in bone cell populations were far removed.…”

Section: Introductionmentioning

confidence: 99%

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Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

2016

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Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone’s capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non-mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness (-8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both p<0.001). Loaded bones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high-dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

2016

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“…Interestingly, a greater increase in trabecular bone volume fraction due to loading was measured in mice scanned four times over 2 weeks compared with mice scanned only once (+140% vs. +88% load‐induced increase, respectively) . These data and subsequent studies suggest that exposure to ionizing radiation from microCT imaging at these doses does not hamper the response of cancellous and cortical bone to mechanical loading.…”

Section: Outcome Measures To Consider For Tibial Loading Studies and mentioning

confidence: 66%

Murine Axial Compression Tibial Loading Model to Study Bone Mechanobiology: Implementing the Model and Reporting Results

Main

Shefelbine

Meakin

et al. 2019

Journal Orthopaedic Research

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In vivo, tibial loading in mice is increasingly used to study bone adaptation and mechanotransduction. To achieve standardized and defined experimental conditions, loading parameters and animal-related factors must be considered when performing in vivo loading studies. In this review, we discuss these loading and animal-related experimental conditions, present methods to assess bone adaptation, and suggest reporting guidelines. This review originated from presentations by each of the authors at the workshop "Developing Best Practices for Mouse Models of In Vivo Loading" during the Preclinical Models Section at the Orthopaedic Research Society Annual Meeting, San Diego, CA, March 2017. Following the meeting, the authors engaged in detailed discussions with consideration of relevant literature. The guidelines and recommendations in this review are provided to help researchers perform in vivo loading experiments in mice, and thus further our knowledge of bone adaptation and the mechanisms involved in mechanotransduction.

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“…Lower numbers of osteoblasts are observed within irradiated bone [36][37][38]43]. Moreover, an increase in reactive oxygen species and associated damage to DNA [44] and related apoptosis is a putative mechanism for cell death [37,39,45,46]. Overall, this effect on osteoblasts and progenitors may lower new matrix (e.g., collagen) production and lead to a reduction in bone density that can increase the risk of fracture [36,[47][48][49][50][51].…”

Section: Mechanisms Of Radiation-induced Bone Changesmentioning

confidence: 99%

“…As expected, tartrate-resistant acid phosphatase (TRAP) 5b, a biomarker for osteoclastic bone resorption that is released from blood and can be quantified from serum, was increased by 1 week in the irradiated mice given placebo compared to non-irradiated mice. Indeed, the efficacy of bisphosphonates (zoledronate) was shown in protecting radiation-induced bone loss in the femurs of mice exposed to a high dose fraction (20 Gy) delivered to the hind limb [59], and reducing biomarkers of bone resorption measured from 45 Ca kinetics late after exposing BALB/c mice to a single 16 Gy fraction that delivered a clinically-relevant biologically effective dose (BED) of 101.3 Gy [60]. However, it should be noted that administration of bisphosphonates has not been efficacious in all rodent models [39].…”

Section: Mechanisms Of Radiation-induced Bone Changesmentioning

confidence: 99%

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity

Farris

Helis

Hughes

et al. 2020

Cancers

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Ionizing radiation is a critical aspect of current cancer therapy. While classically mature bone was thought to be relatively radio-resistant, more recent data have shown this to not be the case. Radiation therapy (RT)-induced bone loss leading to fracture is a source of substantial morbidity. The mechanisms of RT likely involve multiple pathways, including changes in angiogenesis and bone vasculature, osteoblast damage/suppression, and increased osteoclast activity. The majority of bone loss appears to occur rapidly after exposure to ionizing RT, with significant changes in cortical thickness being detectable on computed tomography (CT) within three to four months. Additionally, there is a dose–response relationship. Cortical thinning is especially notable in areas of bone that receive >40 gray (Gy). Methods to mitigate toxicity due to RT-induced bone loss is an area of active investigation. There is an accruing clinical trial investigating the use of risderonate, a bisphosphonate, to prevent rib bone loss in patients undergoing lung stereotactic body radiation therapy (SBRT). Additionally, several other promising therapeutic/preventative approaches are being explored in preclinical studies, including parathyroid hormone (PTH), amifostine, and mechanical loading of irradiated bones.

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Mechanical loading causes site-specific anabolic effects on bone following exposure to ionizing radiation

Cited by 16 publications

References 68 publications

Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

Murine Axial Compression Tibial Loading Model to Study Bone Mechanobiology: Implementing the Model and Reporting Results

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity

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