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

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.