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Event: 2090

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Bone Remodeling

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Bone Remodeling
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Deposition of energy leading to bone loss KeyEvent 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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Bone remodeling is a lifelong process where mature bone tissue is removed by bone resorbing osteoclasts and new bone is formed by bone forming osteoblasts. Each local remodeling event involves a team called the basic multicellular unit (BMU) (Slyfield et al., 2012). Each BMU consists of several morphologically and functionally different cell types, mainly osteoblasts and osteoclasts, that act in coordination on the bone remodeling compartment to replace old bone by new bone.

Physiological bone remodeling, responsible for repairing damaged bone and for mineral homeostasis, is a highly coordinated process that requires balance between bone resorption and bone formation (Raggatt and Partridge, 2010). This tight regulation is necessary to maintain skeletal size, shape, and structural integrity (Raggatt and Partridge, 2010). Mechanical strain or stimulation of bone cells by hormones activates bone remodeling and causes the recruitment of osteoclast precursors, like hematopoietic stem cells (HSCs), to the remodeling site to initiate resorption (Raggatt and Partridge, 2010). Osteocytes, mechanosensory cells that regulate bone homeostasis, basally produce transforming growth factor beta (TGF-β) which inhibits osteoclastogenesis. TGF-β levels are lowered following damage to the bone matrix through osteocyte apoptosis, removing this inhibitory signal (Raggatt and Partridge, 2010). Osteoblasts recruit osteoclast precursors to the remodeling site through the production of monocyte chemoattractant protein-1 (MCP-1). Osteoblasts can then induce osteoclastogenesis through the increased expression of colony stimulating factor 1 (CSF-1) and the receptor activator of nuclear factor kappa B ligand (RANK-L), as well as the decreased expression of osteoprotegerin (OPG), the inhibitor of RANK-L (Donaubauer et al., 2020; Raggatt and Partridge, 2010). Mature osteoclasts produce resorption pits also called resorption bays or Howship’s lacunae (Slyfield et al., 2012). Matrix metalloproteinases (MMPs) secreted by osteoblasts degrade the osteoid lining the bone surface, exposing the bone for osteoclast attachment. A resorption cavity is formed as mature osteoclasts degrade the matrix (Raggatt and Partridge, 2010; Slyfield et al., 2012). The acidic environment produced by osteoclasts dissolves the mineralized matrix, while enzymes like Cathepsin K (CTSK) degrade the organic matrix. Reversal cells then remove the undigested demineralized collagen matrix to prepare for bone formation by osteoblasts. TGF-β acts as the signal for the recruitment of osteoblast progenitor mesenchymal stem cells (MSCs). Osteocytes also basally secrete sclerostin, which inhibits the Wnt pathway for osteoblastogenesis. Mechanical strain and parathyroid hormone (PTH) signaling contribute to suppression of sclerostin and subsequent osteoblastogenesis (Raggatt and Partridge, 2010). Mature osteoblasts create the osteoid (unmineralized) matrix with collagen and subsequently mineralize new bone tissue with hydroxyapatite, involving various enzymes including alkaline phosphatase (ALP) (Donaubauer et al., 2020; Raggatt and Partridge, 2010). 

Disruption to this process results in an imbalance in bone remodeling. For example, increased resorption by osteoclasts and increased mineralization by osteoblasts will increase the rate of bone resorption and decrease the rate of bone formation. 

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Bone remodeling can be measured by the detection of biochemical markers of bone formation and bone resorption in blood serum, dynamic bone histomorphometry in bone biopsies, or via X-ray imaging techniques in vivo. Listed below are common methods for detecting the KE; however, there may be other comparable methods that are not listed.

Method of Measurement 

References 

Description 

OECD Approved Assay 

X-ray and imaging options: 

  • Single-energy x-ray absorptiometry (S[E]XA) 

  • Dual-energy x-ray absorptiometry (D[E]XA) 

  • Single-photon absorptiometry (SPA) 

  • Dual-photon absorptiometry (DPA) 

  • Quantitative computed tomography (QCT) 

Carter, Bouxsein and, Marcus, 1992 

Cummings et al., 2002 

Recurrent imaging of the same bone region in a specific time interval and subsequent overlay of these images, allows for the identification of bone remodeling units and state of bone remodeling.  

No 

Measurements of bone minerals in bodily fluids: 

  • Calcium stable isotope tracers 

  • Spectrophotometry 

  • Ion-sensitive electrode techniques for ionized calcium 

Smith et al., 2005 

Measurement of inorganic skeletal matrix markers such as calcium, phosphorus which, above all, reflect calcium-phosphorus homeostasis and are indicators for the status of bone mineralization.  

No 

Dynamic bone histomorphometry (2D and 3D kinetic measurements) include:  

  • Mineral apposition rate 

  • MAR 

  • Mineral formation rate 

  • Mineralization lag time 

  • Adjusted apposition rate 

  • Osteoid apposition rate 

  • Osteoid maturation time 

  • Bone formation rate 

  • Double-labeled formation events 

  • Formation period 

  • Bone resorption rate 

  • Resorption period 

  • Reversal period 

  • Remodeling period 

  • Quiescent period 

  • Total period 

  • Activation frequency 

  • Structural modeling index (SMI) 

  • Serial block imaging (also known as serial block-face scanning electron microscopy) 

Dempster et al., 2013 

Dynamic histomorphometry comprised the evaluation of bone mineralization from fluorochrome labeled samples. Thus, it is a quantitative measure of bone remodeling in addition to evaluation of bone structure over time. Dynamic histomorphometry can be performed in trabecular and cortical bone.  

No 

Trabeculae measurements: 

  • Rod volume density (Ro.BV/TV)  

  • Plate volume density (Pl.BV/TV) % rod volume fraction (Ro.BV/BV)  

  • % plate volume fraction (Pl.BV/BV)  

  • Rod volume (Ro.V)  

  • Rod surface (Ro.S)  

  • Rod thickness (Ro.Th)  

  • Rod orientation (Ro.θ)  

  • Rod slenderness (Ro.Sl)  

  • Rod mean curvature (Ro.<H>)  

  • Plate volume (Pl.V)   

  • Plate surface (Pl.S)  

  • Plate thickness (Pl.Th)  

  • Plate mean curvature (Pl.<H>) 

Stauber et al., 2006 

Rods and plates forming the trabecular can indicate bone remodeling by altering the bone turnover states (bone formation and resorption) and microarchitecture (Compston, 2016). 

No 

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Taxonomic applicability: Bone remodeling is applicable to all vertebrates such as humans, mice and rats (Bikle and Halloran, 1999; Donaubauer et al., 2020).  

Life stage applicability: There is insufficient data on life stage applicability of this KE. 

Sex applicability: There is insufficient data on sex applicability of this KE. 

Evidence for perturbation by a stressor: Multiple studies show that bone remodeling can be disrupted by many types of stressors including ionizing radiation and altered gravity (Bikle and Halloran, 1999; Donaubauer et al., 2020). 

References

List of the literature that was cited for this KE 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, Springer Nature, https://doi.org/10.1007/s007740050090. 

Carter, D. R., M.L. Bouxsein and R. Marcus (1992), “New Approaches for Interpreting Projected Bone Densitometry Data”, Journal of Bone and Mineral Research, Vol. 7/2, Wiley, https://doi.org/10.1002/jbmr.5650070204. 

Compston, Juliet (2006), “Bone quality: what is it and how is it measured?”, Arquivos Brasileiros de Endocrinologia & Metabologia, Vol. 50/4, https://doi.org/10.1590/S0004-27302006000400003  

Cummings, S. R., D. Bates and D.M. Black (2002), “Clinical Use of Bone Densitometry: Scientific Review”, Journal of the Americal Medical Association, Vol. 288/15, JAMA Network, https://doi.org/10.1001/jama.288.15.1889. 

Dempster, D. W. et al.  (2013), “Standardized Nomenclature, Symbols, and Units for Bone Histomorphometry: A 2012 Update of the Report of the ASBMR Histomorphometry Nomenclature Committee”, Journal of Bone and Mineral Research, Vol. 28, Wiley, https://doi.org/10.1002/jbmr.1805. 

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. 

Raggatt, L. J., and N.C. Partridge (2010), “Cellular and Molecular Mechanisms of Bone Remodeling”, Journal of Biological Chemistry, Vol. 285/33, Elsevier, Amsterdam, https://doi.org/10.1074/jbc.R109.041087 . 

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, S. M., et al. (2005), “Bone Markers, Calcium Metabolism, and Calcium Kinetics during Extended-Duration Space Flight on the Mir Space Station”, Journal of Bone and Mineral Research, Vol. 20/2, Wiley, https://doi.org/10.1359/JBMR.041105. 

Stauber et al. (2006), “Importance of Individual Rods and Plates in the Assessment of Bone Quality and Their Contribution to Bone Stiffness”, Journal of Bone and Mineral Research, Vol. 21/4, Wiley, https://doi.org/10.1359/jbmr.060102. 

Wang, Y. H. et al. (2006), “Examination of Mineralized Nodule Formation in Living Osteoblastic Cultures Using Fluorescent Dyes”, Biotechnology Progress, Vol. 22/6, Wiley, https://doi.org/10.1021/bp060274b