PTH(1–34) treatment and/or mechanical loading have different osteogenic effects on the trabecular and cortical bone in the ovariectomized C57BL/6 mouse

Abstract

In preclinical mouse models, a synergistic anabolic response to PTH(1–34) and tibia loading was shown. Whether combined treatment improves bone properties with oestrogen deficiency, a cardinal feature of osteoporosis, remains unknown. This study quantified the individual and combined longitudinal effects of PTH(1–34) and loading on the bone morphometric and densitometric properties in ovariectomised mice. C57BL/6 mice were ovariectomised at 14-weeks-old and treated either with injections of PTH(1–34); compressive loading of the right tibia; both interventions concurrently; or both interventions on alternating weeks. Right tibiae were microCT-scanned from 14 until 24-weeks-old. Trabecular metaphyseal and cortical midshaft morphometric properties, and bone mineral content (BMC) in 40 different regions of the tibia were measured. Mice treated only with loading showed the highest trabecular bone volume fraction at week 22. Cortical thickness was higher with co-treatment than in the mice treated with PTH alone. In the mid-diaphysis, increases in BMC were significantly higher with loading than PTH. In ovariectomised mice, the osteogenic benefits of co-treatment on the trabecular bone were lower than loading alone. However, combined interventions had increased, albeit regionally-dependent, benefits to cortical bone. Increased benefits were largest in the mid-diaphysis and postero-laterally, regions subjected to higher strains under compressive loads.

Cortical Thickness Adaptive Response to Mechanical Loading Depends on Periosteal Position and Varies Linearly With Loading Magnitude

“…Bone adaptation is a local phenomenon. This has been demonstrated previously along the axis of the tibia or in discrete segments of the tibia (Sugiyama et al, 2010;Lu et al, 2016; Galea et al, 2020;Roberts et al, 2020;Scheuren et al, 2020). However, this work is the first to demonstrate the link between magnitude of axial load and adaptive response around the periosteum of the tibia at a cross-section level.…”

“…To this end, several studies have explored the local cortical thickness variation ( Ct.Th) (Halloran et al, 2002;Stadelmann et al, 2011;Sugiyama et al, 2012;Galea et al, 2015;Birkhold et al, 2016;Roberts et al, 2020), commonly using a minimum distance metric (i.e., the shortest distance between periosteal and endosteal surfaces) (Hildebrand and Rüegsegger, 1997;Bouxsein et al, 2010). Pereira et al (2015) used the same method to analyse Ct.Th but instead considered spatially discrete locations, reporting Ct.Th in a polar coordinate system around the centroid.…”

The Role of the Loading Condition in Predictions of Bone Adaptation in a Mouse Tibial Loading Model

“…The experimental data used in this study were collected in a previously published longitudinal study (Roberts et al, 2020). Six 14-week-old female C57BL6/J were ovariectomized at week 14 of age and underwent in vivo micro-CT scans of the whole right tibia at weeks 14,16,18,20,and 22 (VivaCT80,Scanco Medical,Bruettisellen,Switzerland) with a scanning procedure (55 kVp, 145 µA, 10.4 µm voxel size, 100 ms integration time, 32 mm field of view, 750 projections/180 • , no frame averaging, and 0.5 mm Al filter) that has minimal effects on the bone remodeling (Oliviero et al, 2019).…”

“…Cross-sectional and longitudinal studies have demonstrated that increased passive loading on the skeleton is effective at inducing increased bone formation in aged (Birkhold et al, 2014;Razi et al, 2015a,b) and ovariectomized (Roberts et al, 2019) mouse tibiae, albeit with lower adaptive response than in healthy mice (Melville et al, 2014). In vivo imaging and dynamic 4D (time and space) assessment of bone adaptation enable the detailed evaluation of the lasting benefits of mechanical loading on healthy (Javaheri et al, 2020) and ovariectomized (Roberts et al, 2020) mouse tibia during treatment and after its withdrawal. An understanding of how mechanical loading modifies baseline bone adaptation in response to normal physiological loading will benefit the optimization of treatment strategies to arrest bone loss, improve fracture healing and enhance rehabilitation (Cheong et al, 2020a;Main et al, 2020).…”

“…The purpose of this study was to evaluate the influence of the organ-level load on the local strain distribution across the length of the mouse tibia, and on the accuracy of the predictions of spatial patterns of bone adaptation, morphometric and densitometric properties spatio-temporally with a multiscale approach. The analyses were conducted on mouse tibiae that had been mechanically loaded after OVX (Cheong et al, 2020b;Roberts et al, 2020) using physiological load and/or nominal passive load as applied in the experiments. The novelty of this paper is the comparison among predictions of a micro-FE mechanoregulation pipeline driven by physiological load, applied passive load, and combined physiological-passive load as the source of the mechanical stimulus for bone remodeling.…”