Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.

Diminished bone perfusion develops in response to disuse and has been proposed as a mechanism underlying bone loss. Bone blood flow (BF) has not been investigated within the unique context of severe contusion spinal cord injury (SCI), a condition that produces neurogenic bone loss that is precipitated by disuse and other physiologic consequences of central nervous system injury. Herein, 4-mo-old male Sprague-Dawley rats received T9 laminectomy (SHAM) or laminectomy with severe contusion SCI (N=20/group). Time course assessments of hindlimb bone microstructure and bone perfusion were performed in vivo at 1- and 2-wks post-surgery via microCT and intracardiac microsphere infusion, respectively, and bone turnover indices were determined via histomorphometry. Both groups exhibited cancellous bone loss beginning in the initial post-surgical week, with cancellous and cortical bone deficits progressing only in SCI thereafter. Trabecular bone deterioration coincided with uncoupled bone turnover after SCI, as indicated by signs of ongoing osteoclast-mediated bone resorption and a near-complete absence of osteoblasts and cancellous bone formation. Bone BF was not different between groups at 1-wk, when both groups displayed bone loss. In comparison, femur and tibia perfusion was 30-40% lower in SCI vs SHAM at 2-wks, with the most pronounced regional BF deficits occurring at the distal femur. Significant associations existed between distal femur BF and cancellous and cortical bone loss indices. Our data provide the first direct evidence indicating bone BF deficits develop in response to SCI and temporally coincide with suppressed bone formation and with cancellous and cortical bone deterioration.

IntroductionSpinal cord injury (SCI) produces diminished bone perfusion and bone loss in the paralyzed limbs. Activity-based physical therapy (ABPT) modalities that mobilize and/or reload the paralyzed limbs (e.g., bodyweight-supported treadmill training (BWSTT) and passive-isokinetic bicycle training) transiently promote lower-extremity blood flow (BF). However, it remains unknown whether ABPT alter resting-state bone BF or improve skeletal integrity after SCI.MethodsFour-month-old male Sprague-Dawley rats received T9 laminectomy alone (SHAM; n = 13) or T9 laminectomy with severe contusion SCI (n = 48). On postsurgery day 7, SCI rats were stratified to undergo 3 wk of no ABPT, quadrupedal (q)BWSTT, or passive-isokinetic hindlimb bicycle training. Both ABPT regimens involved two 20-min bouts per day, performed 5 d·wk−1. We assessed locomotor recovery, bone turnover with serum assays and histomorphometry, distal femur bone microstructure using in vivo microcomputed tomography, and femur and tibia resting-state bone BF after in vivo microsphere infusion.ResultsAll SCI animals displayed immediate hindlimb paralysis. SCI without ABPT exhibited uncoupled bone turnover and progressive cancellous and cortical bone loss. qBWSTT did not prevent these deficits. In comparison, hindlimb bicycle training suppressed surface-level bone resorption indices without suppressing bone formation indices and produced robust cancellous and cortical bone recovery at the distal femur. No bone BF deficits existed 4 wk after SCI, and neither qBWSTT nor bicycle altered resting-state bone perfusion or locomotor recovery. However, proximal tibia BF correlated with several histomorphometry-derived bone formation and resorption indices at this skeletal site across SCI groups.ConclusionsThese data indicate that passive-isokinetic bicycle training reversed cancellous and cortical bone loss after severe SCI through antiresorptive and/or bone anabolic actions, independent of locomotor recovery or changes in resting-state bone perfusion.

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BACKGROUND 3D image registration is a technique where in‐vivo microCT scans are collected at different timepoints and regions of interest (ROI) are constructed and aligned to improve the precision of determining bone microstructure. In the rodent spinal cord injury (SCI) model, the rapid bone loss occurring at the distal femur precludes the use of standard 3D registration strategies. PURPOSE To (1) adapt a microCT‐based 3D registration protocol to our rodent SCI model, (2) determine the degree of cancellous bone loss at the distal femoral epiphysis after SCI, and (3) assess the effects of bodyweight‐supported treadmill training (TM) or passive bicycle training (PBT) on bone loss after SCI. METHODS 16‐wk old male Sprague‐Dawley rats were stratified to receive: 1) T9 laminectomy (SHAM) (n=9), 2) severe T9 contusion (SCI) (n=10), 3) SCI+TM (n=10), or 4) SCI+PBT (n=14). TM and PBT began 1‐wk post‐surgery (post‐sx, two 20‐min bouts/day, 5‐d/wk for 3‐wks). In‐vivo microCT scans were performed pre‐sx and 2‐ and 4‐wks post‐sx. Images were aligned with a 3D registration protocol. ROIs were developed to assess cancellous bone microstructure at the distal femoral epiphysis using two separate protocols that either included or excluded new bone formed by periosteal bone expansion over the 4‐wk experiment. RESULTS Differences were noted between the ROI protocols, with the ROI that included periosteal bone growth underestimating SCI‐induced bone loss. As such, the results reported hereafter were derived from the ROI that excluded new bone resulting from periosteal bone expansion. No differences in bone outcomes were present in SHAMs at any timepoint except for a slightly higher trabecular separation (Tb.Sp) at 4‐wks (p<.05). At 2‐wks, SCI displayed 14% lower cancellous bone volume (BV/TV) than pre‐sx (p<.01), characterized by 13% lower trabecular number (Tb.N) (p<.05) and 7% higher Tb.Sp (p<.05). Bone loss was more pronounced at 4‐wks after SCI, evidenced by lower trabecular thickness (Tb.Th) and higher Tb.Sp vs 2‐wks (both p<.01). SCI+TM and SCI+PBT displayed a similar magnitude of bone loss to SCI at 2‐wks (1‐wk after starting exercise). Thereafter, SCI+TM displayed no further bone loss, resulting in 9% less BV/TV loss than SCI (p<.01). In comparison, PBT increased BV/TV 15% from 2‐ to 4‐wks (p<.01), due to 5% higher Tb.Th (p<.01) and 12% higher Tb.N (p<.05), ultimately restoring BV/TV to pre‐sx levels. Structural model index (SMI) and trabecular pattern factor (Tb.Pf) increased in SCI (p<0.05) and SCI+TM at 4‐wks (p<.05 to <.01), signifying transition from rod‐like to weaker plate‐like trabeculae and a less connected trabecular network, respectively. In comparison, SMI (p<.05) and Tb.Pf (p<.01) increased in SCI+PBT at 2‐wks before returning to pre‐sx levels by 4‐wks. CONCLUSION Using our 3D registration protocol, we determined that SCI causes severe cancellous bone loss and changes indicative of an overall weakening of bone architecture at the distal femoral epiphysis. TM attenuated bone loss at this skeletal site, while PBT...