Regional and temporal variation in bone loss during the first year following spinal cord injury.

Osteoporosis is a consequence of spinal cord injury (SCI) that leads to fragility fractures. Visual assessment of bone scans suggests regional variation in bone loss, but this has not been objectively characterised. In addition, substantial inter-individual variation in bone loss following SCI has been reported but it is unclear how to identify fast bone losers. Therefore, to examine regional bone loss, tibial bone parameters were assessed in 13 individuals with SCI (aged 16-76 years). Peripheral quantitative computed tomography scans at 4 % and 66 % tibia length were acquired within 5 weeks, 4 months and 12 months postinjury. Changes in total bone mineral content (BMC), and bone mineral density (BMD) were assessed in ten concentric sectors at the 4 % site. Regional changes in BMC and cortical BMD were analysed in thirty-six polar sectors at the 66 % site using linear mixed effects models. Relationships between regional and total loss at 4 months and 12 months timepoints were assessed using Pearson correlation. At the 4 % site, total BMC (P = 0.001) decreased with time. Relative losses were equal across the sectors (all P > 0.1). At the 66 % site, BMC and cortical BMD absolute losses were similar (all P > 0.3 and P > 0.05, respectively) across polar sectors, but relative loss was greatest in the posterior region (all P < 0.01). At both sites, total BMC loss at 4 months was strongly positively associated with the total loss at 12 months (r = 0.84 and r = 0.82 respectively, both P < 0.001). This correlation was stronger than those observed with 4-month BMD loss in several radial and polar sectors (r = 0.56-0.77, P < 0.05). These results confirm that SCI-induced bone loss varies regionally in the tibial diaphysis. Moreover, bone loss at 4 months is a strong predictor of total loss 12 months postinjury. More studies on larger populations are required to confirm these findings.

Time course changes to structural, mechanical and material properties of bone in rats after complete spinal cord injury.

OBJECTIVE: Characterise the spatiotemporal trabecular and cortical bone responses to complete spinal cord injury (SCI) in young rats. METHODS: 8-week-old male Wistar rats received T9-transection SCI and were euthanised 2-, 6-, 10- or 16-weeks post-surgery. Outcome measures were assessed using micro-computed tomography, mechanical testing, serum markers and Fourier-transform infrared spectroscopy. RESULTS: The trabecular and cortical bone responses to SCI are site-specific. Metaphyseal trabecular BV/TV was 59% lower, characterised by fewer and thinner trabeculae at 2-weeks post-SCI, while epiphyseal BV/TV was 23% lower with maintained connectivity. At later-time points, metaphyseal BV/TV remained unchanged, while epiphyseal BV/TV increased. The total area of metaphyseal and mid-diaphyseal cortical bone were lower from 2-weeks and between 6- and 10-weeks post-SCI, respectively. This suggested that SCI-induced bone changes observed in the rat model were not solely attributable to bone loss, but also to suppressed bone growth. No tissue mineral density differences were observed at any time-point, suggesting that decreased whole-bone mechanical properties were primarily the result of changes to the spatial distribution of bone. CONCLUSION: Young SCI rat trabecular bone changes resemble those observed clinically in adult and paediatric SCI, while cortical bone changes resemble paediatric SCI only.

Spatiotemporal responses of trabecular and cortical bone to complete spinal cord injury in skeletally mature rats.

Objective: Characterise the spatiotemporal responses of trabecular and cortical bone to complete spinal cord injury (SCI) in the skeletally mature rat in the acute (4-week) period following injury. Methods: The spinal cord of 5-month old male rats was transected at the T9 level. Outcome measures were assessed using micro-computed tomography, three-point bending and serum markers at 1-, 2-, and 4-weeks post-transection. Comparison was made with time-0 and sham animals. Results: Lower levels of circulating serum bone formation markers and higher bone resorption markers suggested uncoupled bone turnover as early at 1-week post-transection. Micro-computed tomography showed metaphyseal and epiphyseal trabecular bone loss was observed only at 4-weeks post-transection. The bone loss was site-specific with a more severe reduction in trabecular BV/TV observed in the metaphyseal (50%) relative to epiphyseal (19%) region. Metaphyseal trabecular bone exhibited a 54% reduction in connectivity density while the epiphyseal trabecular bone was unaffected. Cortical bone deficits were not seen over the time periods examined. Conclusions: The study demonstrates that the skeletally mature spinal cord transected rat model replicates the biphasic pattern of osteoporotic changes observed in the human SCI population, providing a relevant model for testing the efficacy of interventions against SCI-induced osteoporosis.

Fibula response to disuse: a longitudinal analysis in people with spinal cord injury.

Fibular response to disuse has been described in cross-sectional but not longitudinal studies. This study assessed fibular bone changes in people with spinal cord injury. Fibular bone loss was less than in the tibia and was not correlated together. This might explain low fibular fracture incidents in these patients. PURPOSE: Cross-sectional studies suggest that the fibula responds differently to loading and disuse compared to the tibia. Whilst tibial bone changes following spinal cord injury (SCI) have been established in longitudinal studies, fibular changes remain unexplored. METHODS: Fibular and tibial bone parameters were assessed in 13 individuals with SCI (aged 16-76 years). Peripheral quantitative computed tomography scans were acquired at 4%, 38% and 66% distal-proximal tibia length at 5 weeks and 12 months post-injury. Changes in 4% site total bone mineral content (BMC), total cross-sectional area (CSA) and bone mineral density (BMD), and 38% and 66% sites total BMC, total CSA, cortical BMD and cortical CSA were assessed using paired T-tests. Relationships between bone loss in the two bones at equivalent sites were assessed using paired T-tests and correlation. RESULTS: At the 4% site, fibular total BMC and BMD losses were less than tibial losses (- 6.9 ± 5.1% and - 6.6 ± 6.0% vs - 14.8 ± 12.4% and - 14.4 ± 12.4%, p = 0.02 and p = 0.03, respectively). Similarly, at the 66% site, fibular BMC losses were less than those in the tibia (- 2.0 ± 2.6% vs - 4.3 ± 3.6%, p = 0.03), but there was no difference at 38% (- 1.8 ± 3.5% vs - 3.8 ± 2.1%, p = 0.1). No correlation was observed for BMC changes between the two bones (all p > 0.25). CONCLUSION: These results support cross-sectional evidence of smaller disuse-related bone loss in the fibula compared to the tibia. These results may in part explain lower incidence of fibula fractures in individuals with chronic SCI. The lack of association between losses in the two bones might point to different underlying mechanisms.

Osteoporosis after spinal cord injury: aetiology, effects and therapeutic approaches.

Osteoporosis is a long-term consequence of spinal cord injury (SCI) that leads to a high risk of fragility fractures. The fracture rate in people with SCI is twice that of the general population. At least 50% of these fractures are associated with clinical complications such as infections. This review article presents key features of osteoporosis after SCI, starting with its aetiology, a description of temporal and spatial changes in the long bones and the subsequent fragility fractures. It then describes the physical and pharmacological approaches that have been used to attenuate the bone loss. Bone loss after SCI has been found to be highly site-specific and characterised by large inter-variability and site-specific changes. The assessment of the available interventions is limited by the quality of the studies and the lack of information on their effect on fractures, but this evaluation suggests that current approaches do not appear to be effective. More studies are required to identify factors influencing rate and magnitude of bone loss following SCI. In addition, it is important to test these interventions at the sites that are most prone to fracture, using detailed imaging techniques, and to associate bone changes with fracture risk. In summary, bone loss following SCI presents a substantial clinical problem. Identification of at-risk individuals and development of more effective interventions are urgently required to reduce this burden.

Global and site-specific analysis of bone in a rat model of spinal cord injury-induced osteoporosis.

Micro-Computed Tomography bone analysis is the gold standard method for assessing trabecular and cortical bone microarchitecture in small animal bones. This technique reports morphometric parameters as averages over selected volumes of interest (VOIs). This study proposes the introduction of an additional global 2D morphometric step into the analysis process, that provides a survey of the underlying morphometric variation present throughout both trabecular and cortical bone. The visualisation of these morphometric distributions provides a systematic approach to VOI selection that provides rationale and adds confidence to subsequent 3D morphometric analysis. To test the applicability and value of this methodological addition it was applied to the distal femur of a rat model of spinal cord injury (SCI)-induced osteoporosis. The 2D morphometric variation of both trabecular and cortical bone was quantified as a function of bone length. SCI-induced osteoporosis was localised in i) trabecular bone, where metaphyseal bone was more severely affected than epiphyseal bone, and there was a significant reduction in Distal Femoral Trabecular Extent, a new parameter defined here that quantifies how far trabecular bone penetrates in to the marrow cavity, ii) cortical bone, where diaphyseal bone underwent significant lowering of both cortical area and thickness, while distal-metaphyseal bone did not. Theses site-specific changes were validated, further elucidated and compared with follow-up conventional 3D analysis. The techniques applied here are equally applicable to other long bones (tibia, humerus, radius, ulna), other types of imaging modality and other types of experimental design including the effects of rehabilitation, aging, loading, gene knockout and pharmacological intervention.

On the relationships between applied force, photography technique, and the quantification of bruise appearance.

Bruising is an injury commonly observed within suspect cases of assault or abuse, yet how a blunt impact initiates bruising and influences its severity is not fully understood. Furthermore, the standard method of documenting a bruise with colour photography is known to have limitations which influence the already subjective analysis of a bruise. This research investigated bruising using a standardised blunt impact, delivered to 18 volunteers. The resulting bruise was imaged using colour, cross polarised (CP) and infrared photography. Timelines of the L*a*b* colour space were determined from both colour and CP images for up to 3 weeks. Overall, no single photographic technique out-performed the others, however CP did provide greater contrast than colour photography. L*a*b* colour space timelines were not attributable any physiological characteristics. Whilst impact force negatively correlated with BMI (R2 = 0.321), neither were associated with any measure of bruise appearance. Due to the inter-subject variability in the bruise response to a controlled infliction, none of the methods in the current study could be used to reliably predict the age of a bruise or the severity of force used in creating a bruise. A more comprehensive approach combining impact characteristics, tissue mechanics, enhanced localised physiological measures and improvements in quantifying bruise appearance is likely to be essential in removing subjectivity from their interpretation.

Patient-specific bone mineral density distribution in the tibia of individuals with chronic spinal cord injury, derived from multi-slice peripheral Quantitative Computed Tomography (pQCT) - A cross-sectional study.

BACKGROUND: The high risk of fracture associated with chronic spinal cord injury (SCI) is attributed to extensive disuse-related bone loss in previously weight-bearing long bones. Changes in bone mineral density (BMD) after SCI have been documented extensively for the epiphyses of the tibia and femur, fracture-prone sites in this patient group. Less attention has been given to patterns of cortical bone loss in the diaphyses, but variability in BMD distributions throughout the long bones may contribute to some patients' increased susceptibility to shaft fractures in chronic SCI. AIM: A cross-sectional study was carried out to determine whether BMD distributions along the tibia differ between individuals with chronic SCI and healthy able-bodied (AB) controls, in both the trabecular and cortical bone compartments. The effects of time post-injury and gender on BMD distribution were also explored. METHODS: Individuals with chronic (≥6months post-injury) motor-complete SCI were recruited from the Queen Elizabeth National Spinal Injuries Unit (Glasgow, UK). AB control subjects were recruited to achieve similar age and gender profiles for the SCI and control groups. Multi-slice pQCT (XCT3000, Stratec) was performed along the length of the tibia (2mm thickness, 0.5mm voxel size), at 1% intervals in the epiphyses and 5% intervals in the diaphysis (34 slices in total). These were used to reconstruct full 3-D subject-specific models (Mimics, Materialise) of BMD distribution, by interpolating between slices. Subjects with chronic SCI were subdivided into 'early' (<4years post-injury) and 'established' SCI (≥4years post-injury). Subject-specific BMD distribution was described according to new parameters determined from the 3-D patient-specific models, quantifying descriptors of the trabecular and cortical BMD regions separately (volume, peak BMD, half-peak width, area under the curve). These were compared between sub-groups (using independent-samples t-tests or Mann-Whitney tests, significance level of 5%). RESULTS: 11 men (age range 17-59years old; mean 35.7±10.6) and 3 post-menopausal women (age range 56-58years old; mean 56.7±1.2years) with motor-complete SCI (ranging from 6months to 27years post-injury) were recruited; 6 men (age range 20-56years old; 33.0±12.7years) and 1 post-menopausal woman (56years) formed the AB control group. Overall, SCI resulted in lower BMD at both trabecular and cortical regions of the tibia. In men, longer time since injury resulted in greater BMD differences when compared to AB, throughout the tibia. For the post-menopausal women, differences in BMD between SCI and AB were greater in cortical bone than in trabecular bone. From the models, individual BMD distribution curves showed healthy double-peaks in AB subjects: one trabecular peak (around 200-300mg/cm3) and the other cortical (around 1000-1100mg/cm3). In most subjects with established SCI, trabecular peaks were exaggerated whilst the cortical peaks were barely discernible, with crucially some individuals already exhibiting a diminishing cortical BMD peak even <4years post-injury. CONCLUSIONS: These findings may have implications for determining the fracture susceptibility of the long bones in individual patients with SCI. Epiphyseal fractures associated with low trabecular BMD are well characterised, but our data show that some individuals with SCI may also be at higher risk of shaft fractures. The proposed BMD distribution description parameters, determined from patient-specific models, could be used to identify patients with a weakened diaphysis who may be susceptible to fractures of the tibial shaft, but this requires validation.

Bone morphology of the femur and tibia captured by statistical shape modelling predicts rapid bone loss in acute spinal cord injury patients.

After spinal cord injury (SCI), bone loss in the paralysed limbs progresses at variable rates. Decreases in bone mineral density (BMD) in the first year range from 1% (slow) to 40% (rapid). In chronic SCI, fragility fractures commonly occur around the knee, with significant associated morbidity. Osteoporosis treatments await full evaluation in SCI, but should be initiated early and targeted towards patients exhibiting rapid bone loss. The potential to predict rapid bone loss from a single bone scan within weeks of a SCI was investigated using statistical shape modelling (SSM) of bone morphology, hypothesis: baseline bone shape predicts bone loss at 12-months post-injury at fracture-prone sites. In this retrospective cohort study 25 SCI patients (median age, 33 years) were scanned at the distal femur and proximal tibia using peripheral Quantitative Computed Tomography at <5 weeks (baseline), 4, 8 and 12 months post-injury. An SSM was made for each bone. Links between the baseline shape-modes and 12-month total and trabecular BMD loss were analysed using multiple linear regression. One mode from each SSM significantly predicted bone loss (age-adjusted P<0.05 R(2)=0.37-0.61) at baseline. An elongated intercondylar femoral notch (femur mode 4, +1 SD from the mean) was associated with 8.2% additional loss of femoral trabecular BMD at 12-months. A more concave posterior tibial fossa (tibia mode 3, +1 SD) was associated with 9.4% additional 12-month tibial trabecular BMD loss. Baseline bone shape determined from a single bone scan is a valid imaging biomarker for the prediction of 12-month bone loss in SCI patients.

Decreases in bone mineral density at cortical and trabecular sites in the tibia and femur during the first year of spinal cord injury.

BACKGROUND: Disuse osteoporosis occurs in response to long-term immobilization. Spinal cord injury (SCI) leads to a form of disuse osteoporosis that only affects the paralyzed limbs. High rates of bone resorption after injury are evident from decreases in bone mineral content (BMC), which in the past have been attributed in the main to loss of trabecular bone in the epiphyses and cortical thinning in the shaft through endocortical resorption. METHODS: Patients with motor-complete SCI recruited from the Queen Elizabeth National Spinal Injuries Unit (Glasgow, UK) were scanned within 5weeks of injury (baseline) using peripheral Quantitative Computed Tomography (pQCT). Unilateral scans of the tibia, femur and radius provided separate estimates of trabecular and cortical bone parameters in the epiphyses and diaphyses, respectively. Using repeat pQCT scans at 4, 8 and 12months post-injury, changes in BMC, bone mineral density (BMD) and cross-sectional area (CSA) of the bone were quantified. RESULTS: Twenty-six subjects (5 female, 21 male) with SCI (12 paraplegic, 14 tetraplegic), ranging from 16 to 76years old, were enrolled onto the study. Repeated-measures analyses showed a significant effect of time since injury on key bone parameters at the epiphyses of the tibia and femur (BMC, total BMD, trabecular BMD) and their diaphyses (BMC, cortical BMD, cortical CSA). There was no significant effect of gender or age on key outcome measures, but there was a tendency for the female subjects to experience greater decreases in cortical BMD. The decreases in cortical BMD in the tibia and femur were found to be statistically significant in both men and women. CONCLUSIONS: By carrying out repeat pQCT scans at four-monthly intervals, this study provides a uniquely detailed description of the cortical bone changes that occur alongside trabecular bone changes in the first year of complete SCI. Significant decreases in BMD were recorded in both the cortical and trabecular bone compartments of the tibia and femur throughout the first year of injury. This study provides evidence for the need for targeted early intervention to preserve bone mass within this patient group.

Prediction of risk of fracture in the tibia due to altered bone mineral density distribution resulting from disuse: a finite element study.

The disuse-related bone loss that results from immobilisation following injury shares characteristics with osteoporosis in post-menopausal women and the aged, with decreases in bone mineral density leading to weakening of the bone and increased risk of fracture. The aim of this study was to use the finite element method to: (i) calculate the mechanical response of the tibia under mechanical load and (ii) estimate of the risk of fracture; comparing between two groups, an able-bodied group and spinal cord injury patients group suffering from varying degrees of bone loss. The tibiae of eight male subjects with chronic spinal cord injury and those of four able-bodied age-matched controls were scanned using multi-slice peripheral quantitative computed tomography. Images were used to develop full three-dimensional models of the tibiae in Mimics (Materialise) and exported into Abaqus (Simulia) for calculation of stress distribution and fracture risk in response to specified loading conditions - compression, bending and torsion. The percentage of elements that exceeded a calculated value of the ultimate stress provided an estimate of the risk of fracture for each subject, which differed between spinal cord injury subjects and their controls. The differences in bone mineral density distribution along the tibia in different subjects resulted in different regions of the bone being at high risk of fracture under set loading conditions, illustrating the benefit of creating individual material distribution models. A predictive tool can be developed based on these models, to enable clinicians to estimate the amount of loading that can be safely allowed onto the skeletal frame of individual patients who suffer from extensive musculoskeletal degeneration (including spinal cord injury, multiple sclerosis and the ageing population). The ultimate aim is to reduce fracture occurrence in these vulnerable groups.

Investigation of robotic-assisted tilt-table therapy for early-stage spinal cord injury rehabilitation.

Damage to the spinal cord compromises motor function and sensation below the level of injury, resulting in paralysis and progressive secondary health complications. Inactivity and reduced energy requirements result in reduced cardiopulmonary fitness and an increased risk of coronary heart disease and cardiovascular complications. These risks may be minimized through regular physical activity. It is proposed that such activity should begin at the earliest possible time point after injury, before extensive neuromuscular degeneration has occurred. Robotic-assisted tilt-table therapy may be used during early-stage spinal cord injury (SCI) to facilitate stepping training, before orthostatic stability has been achieved. This study investigates whether such a stimulus may be used to maintain pulmonary and coronary health by describing the acute responses of patients with early-stage (<1 yr) motor-complete SCI (cSCI) and motor-incomplete SCI (iSCI) to passive, active, and electrically stimulated robotic-assisted stepping. Active participation was found to elicit an increased response from iSCI patients. The addition of electrical stimulation did not consistently elicit further increases. Extensive muscle atrophy was found to have occurred in those patients with cSCI, thereby limiting the potential effectiveness of electrical stimulation. Active participation in robotic-assisted tilt-table therapy may be used to improve cardiopulmonary fitness in iSCI patients if implemented as part of a regular training program.

Role of peripheral quantitative computed tomography in identifying disuse osteoporosis in paraplegia.

OBJECTIVE: Disuse osteoporosis is a major long-term health consequence of spinal cord injury (SCI) that still needs to be addressed. Its management in SCI should begin with accurate diagnosis, followed by targeted treatments in the most vulnerable subgroups. We present data quantifying disuse osteoporosis in a cross-section of the Scottish paraplegic population to identify subgroups with lowest bone mineral density (BMD). MATERIALS AND METHODS: Forty-seven people with chronic SCI at levels T2-L2 were scanned using peripheral quantitative computed tomography at four tibial sites and two femoral sites, at the Queen Elizabeth National Spinal Injuries Unit, Glasgow (UK). At the distal epiphyses, trabecular BMD (BMDtrab), total BMD, total bone cross-sectional area (CSA) and bone mineral content (BMC) were determined. In the diaphyses, cortical BMD, total bone CSA, cortical CSA and BMC were calculated. Bone, muscle and fat CSAs were estimated in the lower leg and thigh. RESULTS: BMDtrab decreased exponentially with time since injury at different rates in the tibia and femur. At most sites, female paraplegics had significantly lower BMC, total bone CSA and muscle CSA than male paraplegics. Subjects with lumbar SCI tended to have lower bone values and smaller muscle CSAs than in thoracic SCI. CONCLUSION: At the distal epiphyses of the tibia and femur, there is generally a rapid and extensive reduction in BMDtrab after SCI. Female subjects, and those with lumbar SCI, tend to have lower bone values than males or those with thoracic SCI, respectively.

Effect of detraining on bone and muscle tissue in subjects with chronic spinal cord injury after a period of electrically-stimulated cycling: a small cohort study.

OBJECTIVE: To investigate adaptive changes in bone and muscle parameters in the paralysed limbs after detraining or reduced functional electrical stimulation (FES) induced cycling following high-volume FES-cycling in chronic spinal cord injury. SUBJECTS: Five subjects with motor-sensory complete spinal cord injury (age 38.6 years, lesion duration 11.4 years) were included. Four subjects stopped FES-cycling completely after the training phase whereas one continued reduced FES-cycling (2-3 times/week, for 30 min). METHODS: Bone and muscle parameters were assessed in the legs using peripheral quantitative computed tomography at 6 and 12 months after cessation of high-volume FES-cycling. RESULTS: Gains achieved in the distal femur by high-volume FES-cycling were partly maintained at one year of detraining: 73.0% in trabecular bone mineral density, 63.8% in total bone mineral density, 59.4% in bone mineral content and 22.1% in muscle cross-sectional area in the thigh. The subject who continued reduced FES-cycling maintained 96.2% and 95.0% of the previous gain in total and trabecular bone mineral density, and 98.5% in muscle cross-sectional area. CONCLUSION: Bone and muscle benefits achieved by one year of high-volume FES-cycling are partly preserved after 12 months of detraining, whereas reduced cycling maintains bone and muscle mass gained. This suggests that high-volume FES-cycling has clinical relevance for at least one year after detraining.

High-volume FES-cycling partially reverses bone loss in people with chronic spinal cord injury.

Spinal cord injury (SCI) leads to severe bone loss in the paralysed limbs and to a resulting increased fracture risk thereof. Since long bone fractures can lead to comorbidities and a reduction in quality of life, it is important to improve bone strength in people with chronic SCI. In this prospective longitudinal cohort study, we investigated whether functional electrical stimulation (FES) induced high-volume cycle training can partially reverse the loss of bone substance in the legs after chronic complete SCI. Eleven participants with motor-sensory complete SCI (mean age 41.9+/-7.5 years; 11.0+/-7.1 years post injury) were recruited. After an initial phase of 14+/-7 weeks of FES muscle conditioning, participants performed on average 3.7+/-0.6 FES-cycling sessions per week, of 58+/-5 min each, over 12 months at each individual's highest power output. Bone and muscle parameters were investigated in the legs by means of peripheral quantitative computed tomography before the muscle conditioning (t1), and after six (t2) and 12 months (t3) of high-volume FES-cycle training. After 12 months of FES-cycling, trabecular and total bone mineral density (BMD) as well as total cross-sectional area in the distal femoral epiphysis increased significantly by 14.4+/-21.1%, 7.0+/-10.8% and 1.2+/-1.5%, respectively. Bone parameters in the femoral shaft showed small but significant decreases, with a reduction of 0.4+/-0.4% in cortical BMD, 1.8+/-3.0% in bone mineral content, and 1.5+/-2.1% in cortical thickness. These decreases mainly occurred between t1 and t2. No significant changes were found in any of the measured bone parameters in the tibia. Muscle CSA at the thigh increased significantly by 35.5+/-18.3%, while fat CSA at the shank decreased by 16.7+/-12.3%. Our results indicate that high-volume FES-cycle training leads to site-specific skeletal changes in the paralysed limbs, with an increase in bone parameters at the actively loaded distal femur but not the passively loaded tibia. Thus, we conclude that high-volume FES-induced cycle training has clinical relevance as it can partially reverse bone loss and thus may reduce fracture risk at this fracture prone site.