This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2848

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Energy Deposition leads to Bone Remodeling

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Energy Deposition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Bone Remodeling

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Deposition of energy leading to occurrence of bone loss	non-adjacent	High	Low	Cataia Ives (send email)	Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	Low	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	Moderate
Unspecific	Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	High
Juvenile	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Bone and bone remodeling cells, like all other tissues and cells, are vulnerable to deposited energy, but with varying radiosensitivity. Ionizing radiation (IR) can indirectly disrupt bone remodeling by depositing energy into bone cells, including osteoblasts, osteoclasts, and osteocytes, resulting in ionization events that can lead to oxidative stress and loss of homeostasis in the bone microenvironment. Changes to bone remodeling cell homeostasis are expressed as a decrease in bone formation and an increase in bone resorption. Bone remodelling can be affected by variety of IR sources, including low linear energy transfer (LET) radiation, such as X-rays, gamma rays, and protons, and high LET radiation, such as heavy ions. These changes can be observed through dynamic bone histomorphometry measurements that quantify the destruction of the organic and inorganic bone matrix by osteoclasts and its replacement by osteoblasts (Dempster et al., 2013). As bone tissue is remodelled, shifts in the proportion of stronger, plate-like trabeculae to more brittle, rod-like trabeculae can be observed through changes to the structural model index (SMI) (Shahnazari et al., 2012).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence on radiation stressors to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The BFR, MAR, and MS/BS are measures of bone formation, and therefore are used as endpoints of bone remodeling. However, studies do not directly measure bone resorption as the bone resorption rate cannot be directly measured by dynamic histomorphometry (Dempster et al., 2013). Instead, studies rely on determining the rate of bone resorption indirectly by observing changes to the BFR relative to changes in bone volume. Future work could be done to identify a direct tissue-level measure of the bone resorption rate.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Modulating Factors	Details	Effects on the KER	References
Drug	Sclerostin (Wnt antagonist) suppression	Chandra et al. (2017) studied the effects of sclerostin on bone remodeling. Sclerostin is a Wnt antagonist, and its expression in adults is primarily restricted to osteocytes. In this experiment, suppression of sclerostin was examined using a monoclonal antibody against sclerostin (Scl-Ab). Data collected from the experiment shows that Scl-Ab completely reverses the effects of radiation on bone tissue. Scl-Ab injections not only blocked any structural deterioration but also increased bone mass and improved bone quality in the irradiated area to the same levels as in a non-irradiated area with Scl-Ab treatment.	Chandra et al., 2017
Age	Old age	Lower estrogen at old age is thought to increase bone resorption, compounding with the effects of radiation.	Pacheco and Stock, 2013

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The following are a few examples of quantitative understanding of the relationship. All data is statistically significant unless otherwise indicated.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Dose Concordance

Reference	Experiment Description	Result
Wright et al., 2015	In vivo. The right hindlimbs of 20-week-old male C57BL/6 mice were irradiated with 2 Gy of X-rays at a rate of 1.6 Gy/min. The bone formation rate normalized to the bone surface (BFR/BS), MS/BS, and MAR were measured 1 week post-irradiation.	Direct radiation with 2 Gy led to a 33% decrease in BFR/BS and a 20% decrease in MS/BS. MAR was decreased by 13% (non-significant).
Chandra et al., 2017	In vivo. The distal metaphyseal region of right femurs of 8- to 10-week-old male mice were irradiated with 8 Gy of X-rays at a rate of 1.65 Gy/min. The SMI, MS, and BFR/BS were measured.	SMI was increased by 26% in irradiated group and MS was decreased by nearly 80% after radiation exposure. BFR/BS levels decreased 100% after irradiation.
Chandra et al., 2014	In vivo. Three-month-old female rats were irradiated at the proximal metaphyseal region of the right tibiae with 16 Gy of X-rays, fractionated into two 8 Gy doses at a rate of 1.65 Gy/min. The SMI, MS/BS, MAR, and BFR/BS were measured.	IR exposure resulted in a 78% decrease in MS/BS and a 100% decrease in both BFR/BS and MAR, as well as a ~20% increase in SMI, at 28 days post-irradiation relative to non-irradiated controls.
Zhang et al., 2019	In vivo. The experiments were performed on 4-week-old male C57BL/6J mice exposed to 2 Gy X-ray radiation at the mid-shaft of the left femur. MS/BS, MAR and BFR/BS were measured.	MS/BS was reduced by 21% in the irradiated group. There was a 22% decrease in BFR/BS in the irradiated group. No changes in MAR, BFR/BS and MS/BS were significant.
Bandstra et al., 2008	In vivo. 58-days old female C57BL/6J mice were exposed to whole-body 0, 0.5,1, or 2 Gy proton radiation of 250 MeV protons at a rate of 0.7 Gy/min. Endosteal BFR (Ec.BFR) was assessed.	Ec.BFR decreased by 19%, 27%, and 21% after 0.5, 1, and 2 Gy, respectively. However, the changes in BFR were not significant.
Xu et al., 2014	In vivo. 8-week-old male Wistar rats were exposed to whole-body 4 Gy X-ray radiation. SMI was measured in the proximal tibia.	SMI was increased in the irradiated group by 105.3% after 4 Gy of X-ray exposure.
Alwood et al., 2010	In vivo. 4-month-old, adult, male, C57BL/6 mice were exposed to irradiation with 0.5 Gy and 2 Gy of 1 GeV/nucleon ⁵⁶Fe heavy ions. SMI was measured in the mineralized cancellous bone tissue of the fourth lumbar vertebrae.	SMI was increased by 194% and 31% (non-significant) after exposure to 2 Gy and 0.5 Gy radiation, respectively.
Hui et al., 2014	In vivo. 20-week-old adult female mice were exposed to a single 16 Gy dose of X-rays to the hindlimbs. The MAR of the distal femurs of irradiated mice was measured.	Compared to non-irradiated controls, irradiation resulted in a 16% decrease per day in MAR at 12-29 days after 16 Gy irradiation.
Kondo et al., 2010	In vivo. 17-week-old C57BL/6J mice were exposed to whole-body 1 or 2 Gy ¹³⁷Cs gamma radiation. Bone remodeling markers such as BFR, MAR, and MS/BS were measured in the proximal tibiae.	Compared to sham-radiated controls, 2 Gy irradiation resulted in a 7% decrease in MS/BS. Changes to BFR and MAR were non-significant.
Zhai et al., 2019	In vivo. 6-week-old male Sprague-Dawley rats were exposed at the left hindlimb to either one single dose of 2 Gy X-ray radiation or fractioned irradiation (3 x 8 Gy) at a dose rate of 185.5 cGy/min. MAR was determined in the irradiated tibia.	MAR did not differ significantly in the 2 Gy irradiated group after 30 and 60 days. MAR was decreased by >50% after 30 days and by 31% (non-significant) after 60 days in the 3 x 8 Gy group.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Time Concordance

Reference	Experiment Description	Result
Wright et al., 2015	In vivo. The right hindlimbs of 20-week-old male C57BL/6 mice were irradiated with 2 Gy of X-rays at a rate of 1.6 Gy/min. BFR/BS, MS/BS, and MAR were measured after 1 week.	Direct radiation with 2 Gy led to a 33% decrease in BFR/BS and a 20% decrease in MS/BS after 1 week. MAR was decreased by 13% (non-significant), also after 1 week.
Chandra et al., 2017	In vivo. The distal metaphyseal region of right femurs of 8- to 10-week-old male mice were irradiated with 8 Gy of X-rays at a rate of 1.65 Gy/min. The SMI, MS, and BFR/BS were measured.	SMI was increased by 26% in the 8 Gy irradiated group and MS was decreased by nearly 80% 4 weeks after radiation exposure. BFR/BS was completely attenuated 4 weeks after irradiation (100% decrease).
Chandra et al., 2014	In vivo. Three-month-old female rats were irradiated at the proximal metaphyseal region of the right tibiae with 16 Gy of X-rays, fractionated into two 8 Gy doses at a rate of 1.65 Gy/min. The SMI, MS/BS, MAR, and BFR/BS were measured.	After 28 days post-irradiation, IR exposure resulted in a 78% decrease in MS/BS and a 100% decrease in both BFR/BS and MAR, as well as a ~20% increase in SMI.
Zhang et al., 2019	In vivo. The experiments were performed on 4-week-old male C57BL/6J mice exposed to 2 Gy X-ray radiation at the mid-shaft of the left femur. MS/BS, MAR and BFR/BS were measured.	MS/BS was reduced by 21% 28 days post-irradiation. There was a 22% decrease in BFR/BS 28 days post-irradiation. No changes in MAR, BFR/BS and MS/BS were significant.
Alwood et al., 2010	In vivo. 4-month-old, adult, male, C57BL/6 mice were exposed to irradiation with 0.5 Gy and 2 Gy of 1 GeV/nucleon ⁵⁶Fe heavy ions. SMI was measured in the mineralized cancellous bone tissue of the fourth lumbar vertebrae.	SMI was increased by 194% and 31% (non-significant) after exposure to 2 Gy (after 31 days) and 0.5 Gy (after 28 days) radiation, respectively.
Zhai et al., 2019	In vivo. 6-week-old male Sprague-Dawley rats were exposed at the left hindlimb to either one single dose of 2 Gy X-ray radiation or fractioned irradiation (3 x 8 Gy) at a dose rate of 185.5 cGy/min. MAR was determined in the irradiated tibia.	MAR did not differ significantly in the 2 Gy irradiated group after 30 and 60 days. MAR was decreased by >50% after 30 days and by 31% (non-significant) after 60 days in the 3 x 8 Gy group.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not Identified

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Supporting evidence for this relationship has been demonstrated in vivo for mice and rats, with considerable evidence for mice. The relationship has been demonstrated in vivo for both males and females, with considerable evidence for males. In vivo evidence is derived from preadolescents, adolescents, and adults, with strong evidence for adolescents and adults.