PTH Treatment Increases Cortical Bone Mass More in Response to Compression than Tension in Mice

Abstract

Parathyroid hormone (PTH) is an anabolic osteoporosis treatment that increases bone mass and reduces fracture risk. Clinically, the effects of PTH are site‐specific, increasing bone mass more at the spine than the hip and not increasing bone mass at the radius. Differences in local loading environment between the spine, hip, and radius may help explain the variation in efficacy, as PTH and mechanical loading have been shown to synergistically increase bone mass. We hypothesized that differences in loading mode might further explain these variations. Owing to the curvature of the mouse tibia, cyclic compression of the hindlimb causes bending at the tibial midshaft, placing the anterior surface under tension and the posterior surface under compression. We investigated the combination of PTH treatment and tibial loading in an osteoblast‐specific estrogen receptor‐alpha knockout mouse model of low bone mass (pOC‐ERαKO) and their littermate controls (LCs) and analyzed bone morphology in the tensile, compressive, and neutral regions of the tibial midshaft. We also hypothesized that pretreating wild‐type C57Bl/6J (WT) mice with PTH prior to mechanical loading would enhance the synergistic anabolic effects. Compression was more anabolic than tension, and PTH enhanced the effect of loading, particularly under compression. PTH pretreatment maintained the synergistic anabolic effect for longer durations than concurrent treatment and loading alone. Together these data provide insights into more effective physical therapy and exercise regimens for patients receiving PTH treatment. © 2022 American Society for Bone and Mineral Research (ASBMR).

The loading direction dramatically affects the mechanical properties of the mouse tibia

“…Investigations into the effect of mechanical loading on bone adaptation in aged mice ( Lynch et al, 2011 ; Birkhold et al, 2014 ; Razi et al, 2015a , 2015b ), ovariectomized mice ( Roberts et al, 2019 , 2020 , 2023 ) and healthy mice ( Melville et al, 2014 ) have shown an increase in bone formation. Furthermore, some studies have looked at increasing the bone anabolic effect of mechanical loading over time on the mouse tibia through the administration of drug treatments, specifically PTH ( Sugiyama et al, 2008 ; Meakin et al, 2017 ; Cheong et al, 2020a ; Roberts et al, 2020 ; Rooney et al, 2023 ), working towards the optimization of combined biomechanical and pharmacological osteoporotic treatments.…”

Strain‐mode‐specific mechanical testing and the interpretation of bone adaptation in the deer calcaneus

“…Strain‐mode‐related CFO differences between the dorsal and plantar cortices of these calcanei are similar to those in “tension cortices” and “compression cortices” of the ovine radius, the equine radius and third metacarpal (MC3), and the proximal diaphysis of human femur (Mason et al., 1995; Riggs, Lanyon, & Boyde, 1993; Riggs, Vaughan, et al., 1993; Skedros et al., 2006, 2013; Skedros, Kiser, & Mendenhall, 2011; Skedros & Kuo, 1999). Though these regional variations likely reflect differential mechano‐responsiveness in habitual strain modes (Ei Hsu Hlaing et al., 2020; Kanzaki et al., 2019; Li et al., 2015; Rooney et al., 2023; Zhong et al., 2013), strain‐magnitude‐dependent remodeling thresholds are also at play because natural bending loads engender strain magnitudes that are typically greater in compression than in tension as shown in many in vivo studies (Fritton & Rubin, 2001; Gross et al., 1992; Judex et al., 1997; Lanyon, 1973; Lieberman et al., 2004; Rubin & Lanyon, 1982; Skedros et al., 2001; Yang et al., 2011).…”