Dose-dependent skeletal deficits due to varied reductions in mechanical loading in rats

Frank C Ko,Daniela Riveros,Mary L Bouxsein,Janice A Nagy,Marie Mortreux,Seward B Rutkove

doi:10.1038/s41526-020-0105-0

Frank C Ko, Daniela Riveros + Show 4 more

Open Access

https://doi.org/10.1038/s41526-020-0105-0

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Abstract

Reduced skeletal loading leads to marked bone loss. Animal models of hindlimb suspension are widely used to assess alterations in skeleton during the course of complete unloading. More recently, the effects of partial unloading on the musculoskeletal system have been interrogated in mice and rats, revealing dose-dependent effects of partial weight bearing (PWB) on the skeleton and skeletal muscle. Here, we extended these studies to determine the structural and functional skeletal alterations in 14-week-old male Wister rats exposed to 20%, 40%, 70%, or 100% of body weight for 1, 2, or 4 weeks (n = 11–12/group). Using in vivo pQCT, we found that trabecular bone density at the proximal tibia declined in proportion to the degree of unloading and continued progressively with time, without evidence of a plateau by 4 weeks. Ex vivo measurements of trabecular microarchitecture in the distal femur by microcomputed tomography revealed deficits in bone volume fraction, 2 and 4 weeks after unloading. Histologic analyses of trabecular bone in the distal femur revealed the decreased osteoblast number and mineralizing surface in unloaded rats. Three-point bending of the femoral diaphysis indicated modest or no reductions in femoral stiffness and estimated modulus due to PWB. Our results suggest that this rat model of PWB leads to trabecular bone deterioration that is progressive and generally proportional to the degree of PWB, with minimal effects on cortical bone.

Highlights

Reduction in mechanical loading occurs in many settings, including cast immobilization, extended bed rest, neuromuscular disorders, spinal cord injury, and spaceflight
Whereas trabecular volumetric BMD (vBMD) remained stable in the PWB100 group over time, longer exposure to unloading led to progressive declines in trabecular vBMD in all groups, with maintenance of the dose-dependent response at all subsequent timepoints (i.e., 2 and 4 weeks; test for trend, p < 0.0001)
By 4 weeks after unloading, trabecular vBMD had declined by 34%, 24%, and 23% from baseline in the PWB20, PWB40, and PWB70 groups, respectively

Summary

Introduction

Reduction in mechanical loading occurs in many settings, including cast immobilization, extended bed rest, neuromuscular disorders, spinal cord injury, and spaceflight. There is a need to develop strategies to mitigate bone loss associated with reduction in mechanical loading. Animal models of reduced mechanical loading have been used to characterize bone loss and evaluate interventions designed to prevent the deleterious effects of unloading. These models include hindlimb unloading, cast immobilization, botulinum toxin administration, and nerve injury[6,7,8,9,10]. While effective in reflecting the musculoskeletal changes that occur with complete immobilization or unloading, these models are limited in their ability to assess musculoskeletal changes due to partial reductions in mechanical loading that occur in many situations. An animal model that could mimic the musculoskeletal effects of fractional gravity, such as that experienced on the Moon or Mars, could provide insights useful for planning future space missions

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