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: 2845

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

Bone Remodeling leads to Bone Loss

Upstream event

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

Bone Remodeling

Downstream event

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

Bone Loss

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	adjacent	Moderate	Low	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed

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
rhesus monkeys	Macaca mulatta	Moderate	NCBI
human	Homo sapiens	Low	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	High
Female	High

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

An imbalance in bone remodeling towards increased resorption of the organic and inorganic components of the bone matrix can lead to an increase in bone loss. Bone remodeling can facilitate bone loss through either stimulating the natural process of resorbing bone matrix back into the blood to facilitate vital processes, or by decreasing the deposition of replacement bone matrix, both of which result in increased bone loss. Changes to bone structure and the subsequent loss of bone results in changes to the portion of bone surface that is actively being mineralized (mineralizing surface, MS/BS). This can lead to measurable changes in the rate at which osteoid seams are mineralized (mineral apposition rate, MAR), and the amount of new bone formed per unit time in relation to the mineralizing surface (bone formation rate, BFR) (Dempster et al., 2013). The structural model index (SMI) of bone tissue, which measures the proportion of rods and plates in trabecular bone, is an important indicator of bone restructuring, with increased rod-like geometry being associated with reduced bone strength (Shahnazari et al., 2012). The resulting bone loss from dysregulated bone remodeling is characterized by deteriorated bone matrix, which is evident in measures of bone structure, including trabecular microarchitecture, cortical microarchitecture, and other measures of static bone histomorphometry, as well as measures of bone strength.

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 Supporting this KER

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

Overall weight of evidence: Moderate

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility supporting the link between bone remodeling and bone loss is highly supported and described well in review papers on the subject (Bikle and Halloran, 1999; Donaubauer et al., 2020; Morey-Holton and Arnaud, 1991; Smith, 2020; Tian et al., 2017). Bone loss is the result of inducing a decrease in bone formation and/or an increase in bone resorption by bone remodeling cells (Willey et al., 2011; Zhang et al., 2008). Osteoblasts generate new bone by secreting collagen and proteoglycans to form the unmineralized, organic bone matrix, and hydroxyapatite crystals to form the mineralized, inorganic component of the matrix (Donaubauer et al., 2020). The organic matrix, or osteoid, contribute strength and stability to bone, while hydroxyapatite crystals provide stiffness (Morey-Holton and Arnaud, 1991). Osteoclasts degrade bone matrix by attaching to the bone surface, forming a sealed resorption pit, and secreting hydrochloric acid to dissolve the hydroxyapatite crystals, as well as proteases such as Cathepsin K (CTSK) and matrix metalloproteinases (MMP9 and MMP14), to degrade the matrix proteins (Smith, 2020; Stavnichuk et al., 2020). Increased demineralization and resorption of bone matrix results in bone mineral density decreasing as organic matrix derivatives and mineral components, such as calcium and phosphorus, are stripped from the bone surface and resorbed into the blood stream (Bikle and Halloran, 1999; Morey-Holton and Arnaud, 1991).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The empirical data relevant to this KER provides strong support for the linkage between bone remodeling and bone loss. Most of the evidence supporting this relationship comes from studies examining the effect of microgravity and X-ray radiation on the skeletal system. Both stressors induce a dose- and time-dependent imbalance in bone remodeling towards increased resorption that results in bone loss (Chandra et al., 2017; Chandra et al., 2014; Hefferan et al., 2003; Hu et al., 2020; Hui et al., 2014; Iwaniec et al., 2005; Iwasaki et al., 2002; Lloyd et al., 2015; Matsumoto et al., 1998; Shahnazari et al., 2012; Wang et al., 2020; Wright et al., 2015; Wronski et al., 1987; Zerath et al., 2002; Zerath et al., 2000).

Incidence Concordance

There is moderate support in current literature for an incidence concordance relationship between bone remodeling and bone loss. Many studies demonstrate an average change to endpoints of bone remodeling that are greater than or equal to that of bone loss (Chandra et al., 2017; Chandra et al., 2014; Hefferan et al., 2003; Hu et al., 2020; Hui et al., 2014; Ishijima et al., 2001; Iwaniec et al., 2005; Lloyd et al., 2015; Willey et al., 2010; Wright et al., 2015; Wronski et al., 1987; Yotsumoto, Takeoka, and Yokoyama, 2010; Zerath et al., 2002; Zerath et al., 2000).

Dose Concordance

Current literature on bone deterioration provides moderate evidence that bone remodeling occurs at lower or the same doses as bone loss. Studies that examine imbalances in bone remodeling caused by space-related stressors, namely ionizing radiation and microgravity, have observed both stressors induce significant decreases in bone formation that are associated with subsequent increases in bone loss. Exposure to microgravity conditions through simulated means, such as hindlimb unloading and tail suspension, or through authentic means, such as spaceflight, resulted in significant decreases in MS, MAR, and BFR, associated with diminished bone volume fraction (BV/TV) and bone mineral density (BMD). Studies that examined the effects of 1-4 weeks of microgravity exposure on mice observed significant decreases in bone remodeling parameters compared to control or baseline levels, from 33-75% for BFR, 33-90% for MAR, and 29% for MS/BS, as well as increases of 0-6% to SMI. These decreases in bone formation were accompanied by degradation to bone structure, as demonstrated by reduced BV/TV (26-82%) and volumetric BMD (vBMD) (12-28%) (Hu et al., 2020; Ishijima et al., 2001; Iwaniec et al., 2005; Lloyd et al., 2015; Shahnazari et al., 2012; Wang et al., 2020; Yotsumoto, Takeoka, and Yokoyama, 2010). Studies that examined microgravity-induced changes in rats after 1-4 weeks of exposure observed decreased MS/BS (70%), BFR (34-80%), MAR (20-50%), as well as increased SMI (9%). These decreases in bone formation were accompanied by bone loss, including 11-69% less BV/TV and 25-45% less BMD (Hefferan et al., 2003; Iwasaki et al., 2002; Matsumoto et al., 1998; Wronski et al., 1987; Zerath et al., 2000).

Studies that utilize ionizing radiation provide the best support for dose-dependence, as they show the variances in bone remodeling and bone loss when exposed to a range of radiation doses. Chandra et al. (2017; 2014) observed significant increases in SMI (~20% and 26%) following irradiation with 8 and 16 Gy of small animal radiation research platform (SARRP) X-rays, indicating a shift in trabecular geometry towards the weaker rod-like trabeculae. This change in the proportion of plates and rods in trabecular bone was associated with decreases to BMD (30% and 14.3%), BV/TV (31% and 17.7%), and trabecular number (Tb.N) (13% and 17.7%), as well as increases in trabecular separation (Tb.Sp) (19% and ~25%), indicating that rod-like trabeculae are more susceptible to bone loss (Chandra et al., 2017; Chandra et al., 2014).

Time Concordance

In the current literature there is limited evidence for a time-dependent relationship between bone remodeling and bone loss. Certain studies examined the effects of microgravity or ionizing radiation-induced bone remodeling on bone loss over a span of time (Hui et al., 2014; Shahnazari et al., 2012). Each study found that changes to their measurement of interest generally increased over time. When examining MAR Hui et al. (2014) observed a decrease by 15.7% per day when measured 12-29 days post-irradiation. They also found a significant decrease in BV/TV at day 30 after exposure to 16 Gy of ionizing radiation (Hui et al., 2014).

After hindlimb unloading, Shahnazari et al. (2012) found that their C57BL/6 and DBA/2 mice both displayed a linear, time-dependent decrease in BV/TV when measured at 1, 2, and 4 weeks, with C57BL/6 mice also exhibiting the same trend in total bone mineral density (BMD/TV). Both bone loss and remodeling showed the first significant decrease after 2 weeks of microgravity (Shahnazari et al., 2012). Bone remodeling and bone loss generally occur at similar time points, with bone remodeling being observed to substantially decrease as early as 1 week of exposure, as demonstrated by the reduction in calcium nodule formation (Hui et al., 2014; Shahnazari et al., 2012). Lima et al. (2017) observed a significant decrease of BFR in 1 Gy irradiated mice 3 days post irradiation. 21 days post irradiation, mice also showed a significant decrease in cancellous bone volume fraction along with a 21% decrease in trabecular bone volume.

Essentiality

Few studies were found that blocked bone remodeling following a stressor and observed the resulting effects on bone loss. Mice exposed to microgravity showed reduced bone formation through decreased MAR and BFR as well as bone loss through decreased BV/TV (Ishijima et al., 2001). Bone remodeling blocked by knockout of osteopontin, a protein that mediates bone remodeling following mechanical stress, resulted in restoration of bone formation and BV/TV (Ishijima et al., 2001). Similarly, inhibition of Calponin h1, a negative regulator of bone formation, restored the indices of bone formation and subsequently increased BMD following microgravity (Yotsumoto, Takeoka, and Yokoyama, 2010).

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

Following exposure to 16 Gy of radiation, mice experienced a significant increase in trabecular BV/TV on day 8 post-irradiation relative to the non-irradiated controls, contrary to the expected outcome of decreased BV/TV (Hui et al., 2014).
Mice exposed to 4.4cGy of X-rays experienced significant decrease in the SMI and a significant increase in trabecular BV/TV compared to the non-irradiated controls, contrary to the expected outcomes of decreased BV/TV and increased SMI (Karim and Judex, 2014).

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 factor	Details	Effects on the KER	References
Genetic	Sclerostin knockout	Sclerostin knockout mice blocked structural deterioration and improved bone quality after radiation.	Chandra et al., 2017
Drug	Parathyroid hormone1-34	Treatment led to a full recovery of all static bone histomorphometric parameters after irradiation.	Chandra et al., 2014
Drug	ODSM	Treatment partially recovered MAR and BV/TV in tibia.	Wang et al., 2020
Drug	Antagomir-132	Partially reversed MAR, BFR and BV/TV and completely reversed BMD.	Hu et al., 2020
Drug	Osteoprotegerin	Treatment reversed spaceflight-induced bone loss.	Lloyd et al., 2015
Genetic	Calponin h1 knockout	Calponin h1 knockout mice showed attenuated bone loss and no significant changes in bone remodeling markers under tail suspension.	Yotsumoto, Takeoka, and Yokoyama, 2010
Genetic	Osteopontin knockout	Osteopontin knockout mice showed no significant changes in bone loss and bone remodeling markers when exposed to a tail suspension model.	Ishijima et al., 2001
Age	Old age	Lower estrogen at old age is thought to contribute to the detrimental effects of radiotherapy on bone loss in elderly patients.	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 represented 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/Incidence Concordance

Reference	Experiment Description	Result
Chandra et al., 2017	In vivo. The femoral metaphyseal osteoblasts and osteocytes of 8- to 10-week-old male mice were irradiated with 8 Gy of focal SARRP X-ray radiation at a rate of 1.65 Gy/min. Histomorphometric parameters including MS, BFR, and SMI for bone remodeling and vBMD, BV/TV, Tb.N, and trabecular separation (Tb.Sp) for bone loss were measured.	Irradiated mice experienced an 86% decrease in MS, a 100% decrease in BFR, and a 26% increase in SMI. The reduction in bone formation and increase in bone resorption was accompanied by a 30% decrease in vBMD, a 31% decrease in BV/TV, a 13% decrease in Tb.N, and a 19% increase in Tb.Sp.
Chandra et al., 2014	In vivo. 3-month-old female rats were irradiated with 16 Gy of SARRP X-rays, fractionated into two 8 Gy doses at a rate of 1.65 Gy/min. Measurements in rat tibiae consisted of indicators of bone remodeling, including MS, BFR, and SMI, and indicators of bone loss, including BMD, BV/TV, Tb.N, and Tb.Sp.	Ionizing radiation exposure resulted in a ~100% decrease in both BFR and MAR, as well as a ~20% increase in SMI, at 28 days post-irradiation relative to non-irradiated controls. The reduction in bone formation was accompanied by a 14.3% decrease in BMD, a 17.7% decrease in BV/TV, a 17.7% decrease Tb.N, and a ~25% increase in Tb.Sp.
Hui et al., 2014	In vivo. 20-week-old adult female mice were irradiated with a single dose of 16 Gy. Measurements in the distal femur included MAR, an indicator of bone remodeling, as well as BV/TV and cortical thickness (Ct.Th), indicators of bone loss.	X-ray irradiation resulted in the mice experiencing a 15.7%/day decrease in MAR from day 12-29 post-irradiation compared to non-irradiated controls. The reduction in bone formation was accompanied by a 0.5-fold decrease in trabecular BV/TV by day 30.
Wright et al., 2015	In vivo. The hindlimbs of 20-week-old adult male mice were irradiated with 2 Gy of X-rays at a rate of 1.6 Gy/min, respectively. Measurements in the tibia and femur consisted of indicators of bone remodeling, including MS and BFR, and the indicator of bone loss, BV/TV.	By 1-week post-irradiation, there was a ~30% and ~52% decrease in BFR and MS, respectively. The decrease in bone formation was accompanied by a 14% and 22% decrease in BV/TV in the distal femur and proximal tibia, respectively, compared to baseline levels.
Willey et al., 2010	In vivo. 20-week-old, adult, female, C57BL/6 mice were exposed to whole body irradiation with 2 Gy of 140 kVp X-rays at a rate of 1.36 Gy/min. Histological measurements were taken from the tibiae to examine the effects of bone remodeling on bone loss. These measurements included BFR, indicator of bone remodeling, and BV/TV, connectivity density (Conn.D), Tb. N, trabecular thickness (Tb. Th), Tb. Sp, vBMD, and Marrow volume (Ma.V), indicators of bone loss.	Following irradiation, the BFR decreased dramatically by 92% after 1 week of irradiation. However, it reached 50% below baseline levels after 3 weeks. This reduction in bone formation was accompanied by a 13% decrease in Tb. N after 1 week, a 15% increase in Tb. Sp after 1 week, and a 21% decrease in vBMD after 3 weeks. There was no significant change in Tb. Th. Additionally, 30% decrease in BV/TV and a 53% decrease in Conn.D in the proximal tibiae after 3 weeks. Ma.V was decreased by 5% at the end of week 3 (non-significant).
Wang et al., 2020	In vivo. 6-month-old male C57BL/6J mice were subjected to 3 weeks of hindlimb unloading. Histological measurements were taken from the distal femurs of the mice to study the effects bone remodeling on bone loss. These measurements included MAR, an indicator of bone remodeling, and BV/TV, an indicator of bone loss.	Following hindlimb unloading, mice experienced a 67% decrease in MAR compared to 1G controls. The decrease in bone formation was accompanied by a 75% decrease in BV/TV.
Hu et al., 2020	In vivo. 6-month-old adult male mice underwent hindlimb unloading for 3 weeks to simulate the effects of microgravity. Histological measurements were taken from the femurs of the mice to study the effects of bone remodeling on bone loss. These measurements consisted of indicators for bone remodeling, including MAR and BFR, and indicators for bone loss, including BMD and BV/TV.	Following hindlimb unloading, mice experienced a ~90% decrease in MAR and a ~75% decrease in BFR compared to baseline levels. The decrease in bone formation was accompanied by a ~28% decrease in BMD and a ~82% decrease in BV/TV.
Lloyd et al., 2015	In vivo. 77-day-old female C57BL/6J mice were exposed to 12 days of spaceflight. Histological measurements were taken from the femur and proximal tibiae of the mice to study the effects of bone remodeling on bone loss. These measurements consisted of indicators of bone remodeling, including MS, MAR, BFR, and SMI, and indicators of bone loss, including BV/TV, cortical volume (Ct.V), and vBMD.	The histology of the spaceflight group was compared against the control and the authors found there was a 33% decrease in periosteal BFR, a 32% decrease in periosteal MS/BS, and a 40% decrease in periosteal MAR. There was also a 40% decrease in endocortical BFR, a 29% decrease in endocortical MS/BS, and a 33% decrease in endocortical MAR. Lastly, there was a 50% decrease in trabecular BFR and a 6% increase in SMI. This reduction in bone formation was accompanied by a 26% decrease in BV/TV, a 7% decrease in femur Ct.V, and a 12% decrease in vBMD.
Shahnazari et al., 2012	In vivo. 6-month-old adult male C57BL/6 and DBA/2 mice underwent hindlimb unloading for 1, 2, and 4 weeks to simulate the effects of microgravity. Measurements of calcified nodules and histological parameters were taken from cultured bone marrow cells and murine femurs, respectively, to study the effects of bone remodeling on bone loss. These histological measurements consisted of indicators of bone remodeling, including BFR, MAR, MS, and SMI, and indicators of bone loss, including BMD, Ct.V, and BV/TV.	While there was no significant change to BFR in C57BL/6 mice, there was a ~33% decrease in DBA/2 mice at 2 weeks post-exposure. After 2 and 4 weeks, DBA/2 mice experienced significant decreases in MS/BS and MAR. SMI did not significantly change following unloading in either model. This reduction in bone formation was accompanied by a progressive decrease in BV/TV, with maximum decreases of 44% and 35% in C57BL/6 and DBA/2 mice, respectively, and significant decreases of ~25% and ~20% at 2 weeks in C57BL/6 and DBA/2 mice, respectively. There was no significant change to Ct.V following unloading.
Iwaniec et al., 2005	In vivo. 70-day-old female C56BL/6 F1 and DBA/2 mice underwent 1 week of hindlimb unloading to simulate microgravity conditions. Histological measurements were taken from the distal femur to study the effects of bone remodeling on bone loss. These measurements included BFR, an indicator of bone remodeling, and bone volume, an indicator of bone loss.	Hindlimb unloading resulted in wild type mice experiencing a 43% decrease in BFR compared to control groups. The decrease in bone formation was accompanied by a 33% decrease in cancellous bone volume.
Hefferan et al., 2003	In vivo. 6-month-old adult rats underwent 14 days of hindlimb unloading to simulate the microgravity conditions. Histological measurements were taken from the tibiae to study the effects of bone remodeling on bone loss. These measurements included BFR and MAR, indicators of bone remodeling, as well as BV/TV and cortical area, indicators of bone loss.	Following hindlimb unloading, there was a ~50% and 33% decrease in MAR in female and male rate, respectively, compared to control groups. There was an 80% decrease in BFR in both male and female rats. This reduction in bone formation was accompanied by an 11% and 18% decrease in BV/TV in female and male mice, respectively. There was no significant change to cortical area between unloaded and ground controls in either male or female rats
Zerath et al., 2002	In vivo. 3- to 4-year-old male rhesus monkeys spent 14 days in spaceflight. Histological measurements of their iliac bone were taken upon landing to study the effects of bone remodeling on bone loss. These measurements consisted of indicators of bone remodeling, including BFR, MAR, and MS, and cancellous bone volume, an indicator of bone loss.	Following microgravity exposure, the monkeys experienced a 33% decrease in MAR, a 53% decrease in BFR, and a 32% decrease in MS/BS compared to pre-flight values. This reduction in bone formation was accompanied by a 35% decrease in BV/TV.
Iwasaki et al., 2002	In vivo. 13-week-old adult male rats underwent 4 weeks of tail suspension to simulate microgravity conditions. Histological measurements were taken from the tibiae of the rats to study the effects of bone remodeling on bone loss. These measurements consisted of indicators of bone remodeling, including BFR and MAR, and indicators of bone loss, including BV/TV and BMD.	Following tail suspension, there was a 20% decrease in MAR and a 39% decrease in BFR in rat tibiae compared to non-suspended controls. This reduction in bone formation was accompanied by a 45% decrease in tibiae BMD and a 69% decrease in BV/TV.
Zerath et al., 2000	In vivo. 9-week-old juvenile male rats were exposed to 17 days of spaceflight and histological measurements were taken from pelvic tissue upon landing to study the effects of bone remodeling on bone loss. These measurements included BFR and MAR, indicators of bone remodeling, and BV/TV, an indicator of bone loss.	Microgravity exposure resulted in a 52% decrease in BFR and a 34% decrease in MAR compared to the animal enclosure model (AEM) ground control. This reduction in bone formation was accompanied by a 12% decrease in BV/TV compared to the AEM ground control.
Matsumoto et al., 1998	In vivo. 6-week-old juvenile male rats underwent tail suspension for 14 days to simulate microgravity conditions. Histological measurements of the femur and tibiae were taken to study the effects of bone remodeling on bone loss. These measurements included MAR, an indicator of bone remodeling, as well as BMD and BV/TV, indicators of bone loss	Tail suspension resulted in a 48% decrease in periosteal MAR in the femur compared to baseline levels. This reduction in bone formation was accompanied by a 67% decrease in tibial BV/TV compared to baseline levels. The average of BMD levels across multiple regions of the femur were also significantly reduced.
Wronski et al., 1987	In vivo. 84-day-old adult male rats were exposed to 7 days of spaceflight and histological measurements were taken from their tibiae to study the effect of bone remodeling on bone loss. These measurements included periosteal BFR, an indicator of bone remodeling, and trabecular bone volume, an indicator of bone loss.	Microgravity resulted in a 34% decrease compared to the ground controls. The reduction in bone formation was accompanied by a 28% decrease in trabecular bone volume compared to ground controls.
Yang et al., 2020	In vivo. Male 14-week-old transgenic mice were unloaded using tail suspension. The tibia of wildtype and transgenic mice were scanned at 28 days after un-loading. Bone remodeling markers such as MAR, BFR, and MS/BS were measured. BV/TV was used as a bone loss marker.	Following hindlimb unloading, there was a 23% decrease in MAR, a 33% decrease in BFR, and a 50% decrease in MS/BS under microgravity relative to control. This was accompanied by a 58% decrease in BV/TV.
Yotsumoto, Takeoka, and Yokoyama, 2010	In vivo. Eight-week-old male mice were tail-suspended. MAR, and BFR as bone remodeling markers and BV/TV and BMD as bone loss markers were measured.	75% decrease in MAR and 50% decrease in BFR under tail suspension was accompanied by a 50% decrease in BV/TV and a 25% decrease in BMD.
Ishijima et al., 2001	In vivo. Female 12-week-old mice were tail-suspended. MAR, and BFR as bone remodeling markers and BV/TV as bone loss marker were measured.	68% decrease in BFR and a 40% decrease in MAR in tail-suspended mice. This was accompanied by a 50% decrease in BV/TV.

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

References	Experiment Description	Result
Hui et al., 2014	In vivo. 16-week-old adult female mice were irradiated with a single dose of 16 Gy. Histological measurements of the distal femurs of the mice were taken to study the effects of bone remodeling on bone loss. These measurements included MAR, an indicator of bone remodeling (upstream KE), and BV/TV, an indicator of bone loss (downstream KE).	X-ray irradiation resulted in the mice experiencing a 15.7%/day decrease in MAR from day 12-29 post-irradiation compared to non-irradiated controls. Trabecular BV/TV decreased 0.5-fold at day 30.
Shahnazari et al., 2012	In vivo. 6-month-old adult male C57BL/6 and DBA/2 mice underwent hindlimb unloading for 1, 2, and 4 weeks to simulate the effects of microgravity. Measurements of calcified nodules and histological parameters were taken from cultured bone marrow cells and murine femurs, respectively, to study the effects of bone remodeling on bone loss. The histological measurements consisted of indicators of bone remodeling, including BFR, MAR, and MS, and indicators of bone loss, including BMD and BV/TV.	DBA/2 mice only experienced a significant decrease in BFR at 2 weeks. BFR in C57BL/6 mice did not change significantly at any time point. MS/BS and MAR both showed significant decreases in DBA/2 mice at 2 and 4 weeks. Both BV/TV and BMD/TV decreased in a linear, time-dependent manner in C57BL/6 mice with significant decreases at 2 and 4 weeks. Reductions in the BV/TV of DBA/2 mice also followed a linear, time-dependent trend, with significant decreases at 2 and 4 weeks. DBA/2 mice only saw a significant decrease in BMD/TV at 2 weeks.
Lima et al., 2017	In vivo, 4-month-old female BALB/cBYJ mice were administered 0,0.17,0.5, and 1 Gy of X-ray radiation. Histomorphometry analysis and fluorochrome labeling was used to measure BFR. BV/TV was analyzed using micro-computed tomography (micro-CT).	1 Gy of radiation significantly decreased bone formation rate 3 days post-irradiation. At 21 days post-irradiation, a significant decrease in cancellous bone volume fraction occurred, along with a 21% decrease in trabecular bone volume.

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

Evidence for this relationship has been demonstrated in vivo for monkeys, mice, and rats, with considerable evidence from mice and rats. The relationship has been demonstrated in vivo for both males and females, with considerable evidence for both. There is in vivo evidence in adolescent and adult animals, with considerable evidence for both. However, less evidence supports a decrease in bone formation in mature animal models or humans.

References

List of the literature that was cited for this KER description. More help

Bikle, D. D. and B. P. Halloran. (1999), "The response of bone to unloading", Journal of Bone and Mineral Metabolism, Vol. 17/4, Nature, https://doi.org/10.1007/s007740050090.

Chandra, A. et al. (2017), "Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms", Journal of Bone and Mineral Research, Vol. 32/2, Wiley, https://doi.org/10.1002/jbmr.2996.

Chandra, A. et al. (2014), "PTH1-34 Alleviates Radiotherapy-induced Local Bone Loss by Improving Osteoblast and Osteocyte Survival", Bone, Vol. 67/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.bone.2014.06.030.PTH1-34.

Donaubauer, A. J. et al. (2020), "The influence of radiation on bone and bone cells—differential effects on osteoclasts and osteoblasts", International Journal of Molecular Sciences, Vol. 21/17, MDPI, Basel, https://doi.org/10.3390/ijms21176377.

Frost H. M. (1966), “Bone dynamics in metabolic bone disease” The Journal of bone and joint surgery. American volume, 48(6), 1192–1203.

Hefferan, T. E. et al. (2003), "Effect of gender on bone turnover in adult rats during simulated weightlessness", Journal of Applied Physiology, Vol. 95/5, American Physiological Society, https://doi.org/10.1152/japplphysiol.00455.2002.

Hu, Z. et al. (2020), "Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice", Stem Cell Research and Therapy, Vol. 11/1, Nature, https://doi.org/10.1186/s13287-020-1581-6.

Hui, S. K. et al. (2014), "The Influence of Therapeutic Radiation on the Patterns of Bone Remodeling in Ovary-Intact and Ovariectomized Mice", Calcified Tissue International, Vol. 23/1, Nature, https://doi.org/10.1007/s00223-012-9688-0

Ishijima, M. et al. (2001), “Enhancement of Osteoclastic Bone Resorption and Suppression of Osteoblastic Bone Formation in Response to Reduced Mechanical Stress Do Not Occur in the Absence of Osteopontin”, The Journal of Experimental Medicine, Vol. 193/3, https://doi.org/10.1084/jem.193.3.399.

Iwaniec, U. T. et al. (2005), "Effects of disrupted β1-integrin function on the skeletal response to short-term hindlimb unloading in mice", Journal of Applied Physiology, Vol. 98/2, American Physiological Society, https://doi.org/10.1152/japplphysiol.00689.2004.

Iwasaki, Y. et al. (2002), "Maintenance of trabecular structure and bone volume by vitamin K 2 in mature rats with long-term tail suspension", Journal of Bone and Mineral Metabolism, Vol. 20/4, Nature, https://doi.org/10.1007/s007740200031.

Karim, L. and S. Judex. (2014), “Low level irradiation in mice can lead to enhanced trabecular bone morphology”, Journal of bone and mineral metabolism, Vol. 32/5, 476–483. https://doi.org/10.1007/s00774-013-0518-x

Lima, F. et al. (2017). Exposure to Low-Dose X-Ray Radiation Alters Bone Progenitor Cells and Bone Microarchitecture. Radiation Research, 188(4.1), 433–442. http://www.jstor.org/stable/26428489

Lloyd, S. A. et al. (2015), "Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice", Bone, Vol. 81, Elsevier, https://doi.org/10.1016/j.bone.2015.08.021.

Matsumoto, T. et al. (1998), "Effect of mechanical unloading and reloading on periosteal bone formation and gene expression in tail-suspended rapidly growing rats", Bone, Vol. 22/5, Elsevier, https://doi.org/10.1016/S8756-3282(98)00018-0.

Morey-Holton, E. and S. B. Arnaud. (1991), "NASA Technical Memorandum 103890".

Pacheco, R. and H. Stock. (2013), "Effects of Radiation on Bone", Current Osteoporosis Reports, Vol. 11/4, Nature, https://doi.org/10.1007/s11914-013-0174-z

Shahnazari, M. et al. (2012), "Simulated spaceflight produces a rapid and sustained loss of osteoprogenitors and an acute but transitory rise of osteoclast precursors in two genetic strains of mice", American Journal of Physiology - Endocrinology and Metabolism, Vol. 303/11, American Physiological Society, https://doi.org/10.1152/ajpendo.00330.2012.

Slyfield, C. R., et al. (2012), “Three-dimensional dynamic bone histomorphometry”, Journal of bone and mineral research, Vol. 27/2, Wiley, https://doi.org/10.1002/jbmr.553.

Smith, J. K. (2020), "Osteoclasts and microgravity", Life, Vol. 10/9, MDPI, Basel, https://doi.org/10.3390/life10090207.

Stavnichuk, M., et al. (2020), “A systematic review and meta-analysis of bone loss in space travelers”, NPJ microgravity, Vol. 6, Nature, https://doi.org/10.1038/s41526-020-0103-2

Tian, Y. et al. (2017), "The Impact of Oxidative Stress on the Bone System in Response to the Space Special Environment", The International Journal of Molecular Sciences, Vol. 18/10, MDPI, Basel, https://doi.org/10.3390/ijms18102132.

Wang, Y. et al. (2020), "Targeted Overexpression of the Long Noncoding RNA ODSM can Regulate Osteoblast Function In Vitro and In Vivo", Cell Death and Disease, Vol. 11, Springer Nature, Berlin, https://doi.org/10.1038/s41419-020-2325-3.

Willey, J. S. et al. (2011), "Ionizing Radiation and Bone Loss: Space Exploration and Clinical Therapy Applications", Clinical Reviews in Bone and Mineral Metabolism, Vol. 9, Nature, https://doi.org/10.1007/s12018-011-9092-8.

Willey, J. S. et al. (2010), "Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations", Bone, Vol. 46/1, Elsevier, https://doi.org/10.1016/j.bone.2009.09.002.

Wright, L. E. et al. (2015), "Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model", Journal of Bone and Mineral Research, Vol. 30/7, Wiley, https://doi.org/10.1002/jbmr.2458

Wronski, T. J. et al. (1987), "Histomorphometric analysis of rat skeleton following spaceflight", American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 252/2, American Physiological Society, https://doi.org/10.1152/ajpregu.1987.252.2.r252.

Yang, J. et al. (2020), "Blocking Glucocorticoid Signaling in Osteoblasts and Osteocytes Prevents Mechanical Unloading-Induced Cortical Bone Loss", Bone, Elsevier, Amsterdam, https://doi.org/10.1016/j.bone.2019.115108.

Yotsumoto, N., M. Takeoka and M. Yokoyama. (2010), "Tail-suspended mice lacking calponin H1 experience decreased bone loss.", The Tohoku journal of experimental medicine, Vol. 221/3, Tohoku University Medical Press, Tohoku, https://doi.org/10.1620/tjem.221.221.

Zérath, E. et al. (2002), "Spaceflight affects bone formation in rhesus monkeys: A histological and cell culture study", Journal of Applied Physiology, Vol. 93/3, American Physiological Society, https://doi.org/10.1152/japplphysiol.00610.2001.

Zerath, E. et al. (2000), "Spaceflight inhibits bone formation independent of corticosteroid status in growing rats", Journal of Bone and Mineral Research, Vol. 15/7, Wiley, https://doi.org/10.1359/jbmr.2000.15.7.1310.

Zhang, P. et al. (2008), “A brief review of bone adaptation to unloading.” Genomics, proteomics and bioinformatics, Vol. 6/1, Elsevier, Amsterdam, https://doi.org/10.1016/S1672-0229(08)60016-9