Monthly treatment with romosozumab for 1 year increases bone mineral at the hip, but not the knee, in women with chronic spinal cord injury.

Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI). To date, most research has focused on pharmaceutical intervention using antiresorptives to prevent bone loss during the acute phase of SCI; however, limited research has investigated treatments for established osteoporosis during chronic SCI. Romosozumab, a monoclonal antibody with both antiresorptive and anabolic effects, has demonstrated significant increases in BMD for women with established PMO. Therefore, the purpose of this study was to examine the efficacy of monthly treatment with romosozumab to improve DXA-derived areal BMD at the hip, and CT-derived BMC and strength at the hip and knee in women with chronic SCI and an inability to ambulate. Twelve female participants with chronic SCI were recruited to receive 1 yr of monthly subcutaneous injections of romosozumab (210 mg). DXA and CT scans were taken at baseline, and months 3, 6, and 12 to quantify bone mineral, and finite element (FE) analysis was used to predict bone strength. Longitudinal mixed effects models were employed to determine the impact of treatment on bone properties. After 12 mo of treatment, areal BMD at the lumbar spine and total hip were significantly increased with median changes of 10.2% (IQR: 8.3-15.2%, p<.001) and 4.2% (IQR: 3.4-7.7%, p = .009), respectively. Improvements at the hip were primarily due to increases in trabecular, not cortical, bone and effects were sufficient to significantly increase FE-predicted strength by 20.3% (IQR: 9.5-37.0%, p = .004). Treatment with romosozumab did not lead to any significant improvement in bone mineral at the distal femur or proximal tibia. These findings provide promising results for romosozumab treatment to improve bone mineral and reduce fracture risk at the hip, but not the knee, in women with chronic SCI.

Zoledronic acid after spinal cord injury mitigates losses in proximal femoral strength independent of ambulation ability.

Rapid bone loss can occur after spinal cord injury (SCI) and a standard of care to prevent or treat this phenomenon is an active area of research. Using advanced analysis techniques, this study demonstrates that zoledronic acid, a possible treatment, prevented loss of bone strength at the hip following SCI. INTRODUCTION: Bone loss below the level of neurological lesion is a well-known complication of spinal cord injury (SCI), and effective preventive treatment for this phenomenon is an active area of research. Zoledronic acid has demonstrated efficacy to attenuate bone loss at the hip after SCI, but previous studies relied on measurements from dual-energy X-ray absorptiometry. The purpose of this investigation was to more thoroughly characterize changes to bone mineral and strength at the proximal femur in individuals receiving zoledronic acid in the acute SCI stage; we also examined the influence of ambulatory ability on bone outcomes. METHODS: Participants randomized to either zoledronic acid (n = 29) or placebo (n = 30) received computed tomography (CT) scans and ambulatory assessments at baseline and 6 and 12 months following drug infusion. CT-based finite element (FE) modeling was used to predict changes in proximal femoral strength associated with treatment. RESULTS: After 12 months, FE-predicted bone strength was reduced by a mean (SD) of 9.6 (17.9)% in the zoledronic acid group versus 24.6 (24.5)% in the placebo group (p = 0.007). These differences in strength were explained by reductions in CT measurements of both trabecular (p < 0.001) and cortical (p ≤ 0.021) bone at the femoral neck and trochanteric region. Ambulation ability influenced select trabecular and cortical parameters, but we were unable to detect an impact on FE-predicted bone strength. CONCLUSION: These findings demonstrate that treatment with zoledronic acid in acute SCI attenuates losses in proximal femoral strength, which may reduce the risk of hip fractures across patients with varying degrees of ambulatory abilities.

Bone Mineral Loss at the Distal Femur and Proximal Tibia Following Spinal Cord Injury in Men and Women.

PURPOSE: Spinal cord injury (SCI) causes rapid bone loss and increases risk of fragility fractures in the lower extremities. The majority of individuals with SCI are men, and few studies have investigated sex as a biological variable in SCI-induced osteoporosis. This cross-sectional study aimed to quantify sex-specific differences in bone mineral following SCI. METHODS: Quantitative computed tomography (QCT) scans of the distal femur and proximal tibia were obtained at baseline of one of four clinical trials enrolling people who sustained SCI 1 month to 50 years prior to recruitment. Bone volume (BV), bone mineral content (BMC), bone mineral density (BMD), and bending strength index (BSI) were quantified in the integral, trabecular, and cortical bone in the epiphysis, metaphysis and diaphysis. Scans from 106 men and 31 women were analyzed to measure sex-specific effects on bone loss over time post-SCI. RESULTS: BMC and BSI declined exponentially as a function of time post-SCI and were best described by separate decay curves for men and women. Women had BV, BMC, and BSI at 58-77% that of men in the acute and plateau phases, with both sexes showing similar rates of loss as a function of time post-SCI. Trabecular BMD was best described as an exponential decay versus time post-SCI, with no sex-specific differences. CONCLUSIONS: Due to consistently lower BV, BMC, and BSI, women may be more susceptible to fractures after SCI than men.

Durability and delayed treatment effects of zoledronic acid on bone loss after spinal cord injury: a randomized, controlled trial.

A single infusion of zoledronic acid (ZOL) after acute spinal cord injury (SCI) attenuates bone loss at the hip (proximal femur) and knee (distal femur and proximal tibia) for at least 6 months. The objective of this study was to examine the effects of timing and frequency of ZOL over 2 years. In this double-blind, placebo-controlled trial, we randomized 60 individuals with acute SCI (<120 days of injury) to receive either ZOL 5-mg infusion (n = 30) or placebo (n = 30). After 12 months, groups were again randomized to receive ZOL or placebo, resulting in four treatment groups for year 2: (i) ZOL both years; (ii) ZOL year 1, placebo year 2; (iii) placebo year 1, ZOL year 2; and (iv) placebo both years. Our primary outcome was bone loss at 12 months; compared to placebo, a single infusion of ZOL attenuated bone loss at the proximal femur, where median changes relative to baseline were -1.7% to -2.2% for ZOL versus -11.3% to -12.8% for placebo (p < 0.001). Similarly, the distal femur and proximal tibia showed changes of -4.7% to -9.6% for ZOL versus -8.9% to -23.0% for placebo (p ≤ 0.042). After 24 months, differences were significant at the proximal femur only (-3.2% to -6.0% for ZOL vs. -16.8% to -21.8% for placebo; p ≤ 0.018). Although not statistically significant, median bone density losses suggested some benefit from two annual infusions compared to a single baseline infusion, as well as from a single infusion 12 months after baseline compared to 2 years of placebo; therefore, further investigation in the 12-month to 24-month treatment window is warranted. No unanticipated adverse events associated with drug treatment were observed. In summary, ZOL 5-mg infusion after acute SCI was well-tolerated and may provide an effective therapeutic approach to prevent bone loss in the first few years following SCI. © 2021 American Society for Bone and Mineral Research (ASBMR).

Stiffness and Strength Predictions From Finite Element Models of the Knee are Associated with Lower-Limb Fractures After Spinal Cord Injury.

Spinal cord injury (SCI) is associated with bone fragility and fractures around the knee. The purpose of this investigation was to validate a computed tomography (CT) based finite element (FE) model of the proximal tibia and distal femur under biaxial loading, and to retrospectively quantify the relationship between model predictions and fracture incidence. Twenty-six cadaveric tibiae and femora (n = 13 each) were loaded to 300 N of compression, then internally rotated until failure. FE predictions of torsional stiffness (K) and strength (Tult) explained 74% (n = 26) and 93% (n = 7) of the variation in experimental measurements, respectively. Univariate analysis and logistic regression were subsequently used to determine if FE predictions and radiographic measurements from CT and dual energy X-ray absorptiometry (DXA) were associated with prevalent lower-limb fracture in 50 individuals with SCI (n = 14 fractures). FE and CT measures, but not DXA, were lower in individuals with fracture. FE predictions of Tult at the tibia demonstrated the highest odds ratio (4.98; p = 0.006) and receiver operating characteristic (0.84; p = 0.008) but did not significantly outperform other metrics. In conclusion, CT-based FE model predictions were associated with prevalent fracture risk after SCI; this technique could be a powerful tool in future clinical research.

Open-label clinical trial of alendronate after teriparatide therapy in people with spinal cord injury and low bone mineral density.

STUDY DESIGN: Non-randomized open-label clinical trial of oral alendronate after teriparatide therapy in people with spinal cord injury (SCI) and low bone mineral density (BMD). OBJECTIVES: To determine if alendronate would prevent bone loss after discontinuation of teriparatide. SETTING: Outpatient research clinic at Northwestern University Feinberg School of Medicine. METHODS: Seventeen participants with chronic SCI who recently completed 12-24 months of teriparatide treatment received oral alendronate 70 mg once weekly for 12 months. Participants were evaluated at baseline, 6 months and 12 months. Bone was assessed by: DXA at the spine and hip, CT at the distal femur/proximal tibia, serum collected for bone markers, and bone strength determined by finite element (FE) analysis of the proximal tibia. RESULTS: Areal BMD showed no significant change from baseline at the total hip or femoral neck, where mean change (SD) was 1.3% (4.7) and 0.54% (5.0), respectively. However, areal BMD increased significantly at the spine by 2.5% (4.6). CT demonstrated significant increases in bone mineral content at the femoral epiphysis, metaphysis, and diaphysis, 15% (18), 7.7% (12), and 3.0% (3.5), respectively. Measurements at the tibia illustrated improvements and reductions, but no changes to FE-predicted strength were observed. Biomarkers illustrated inhibition of bone formation and resorption, with P1NP and CTX decreasing by 52% (82) and 62% (74), respectively. CONCLUSION: Twelve months of alendronate after discontinuation of teriparatide in people with SCI can prevent bone loss and may increase bone mass and preserve bone strength at the spine, hip, and some sites of the knee.

Effects of Teriparatide and Vibration on Bone Mass and Bone Strength in People with Bone Loss and Spinal Cord Injury: A Randomized, Controlled Trial.

Spinal cord injury (SCI) is associated with marked bone loss and an increased risk of fracture. We randomized 61 individuals with chronic SCI and low bone mass to receive either teriparatide 20 µg/d plus sham vibration 10 min/d (n = 20), placebo plus vibration 10 min/d (n = 20), or teriparatide 20 µg/d plus vibration 10 min/d (n = 21). Patients were evaluated for 12 months; those who completed were given the opportunity to participate in an open-label extension where all participants (n = 25) received teriparatide 20 µg/d for an additional 12 months and had the optional use of vibration (10 min/d). At the end of the initial 12 months, both groups treated with teriparatide demonstrated a significant increase in areal bone mineral density (aBMD) at the spine (4.8% to 5.5%). The increase in spine aBMD was consistent with a marked response in serum markers of bone metabolism (ie, CTX, P1NP, BSAP), but no treatment effect was observed at the hip. A small but significant increase (2.2% to 4.2%) in computed tomography measurements of cortical bone at the knee was observed in all groups after 12 months; however, the magnitude of response was not different amongst treatment groups and improvements to finite element-predicted bone strength were not observed. Teriparatide treatment after the 12-month extension resulted in further increases to spine aBMD (total increase from baseline 7.1% to 14.4%), which was greater in patients initially randomized to teriparatide. Those initially randomized to teriparatide also demonstrated 4.4% to 6.7% improvements in hip aBMD after the 12-month extension, while all groups displayed increases in cortical bone measurements at the knee. To summarize, teriparatide exhibited skeletal activity in individuals with chronic SCI that was not augmented by vibration stimulation. Without additional confirmatory data, the location-specific responses to teriparatide would not be expected to provide clinical benefit in this population. © 2018 American Society for Bone and Mineral Research.

Assessment of Paraspinal Muscle Cross-sectional Area After Lumbar Decompression: Minimally Invasive Versus Open Approaches.

STUDY DESIGN: A retrospective, blinded analysis of imaging studies. SUMMARY OF BACKGROUND DATA: To evaluate changes in paraspinal muscle cross-sectional area (CSA) after surgical treatment for lumbar stenosis and to compare these changes between minimally invasive and standard open approaches. The open approach to lumbar stenosis is effective, but it involves retraction and resection of muscle from the spinous process, which can result in ischemia and denervation of paraspinal musculature and may lead to muscle atrophy and pain. OBJECTIVE: It is hypothesized that the microendoscopic decompression of stenosis (MEDS) technique will better preserve the paraspinal muscles compared with the open procedure. MATERIALS AND METHODS: A total of 18 patients underwent a 1-level posterior decompression for lumbar stenosis, (9 open, 9 MEDS). Lumbar magnetic resonance imaging was obtained before surgery and after surgery (open approach average 16.3 mo; MEDS average 16.6 mo). CSA of paraspinal muscles were averaged over the distance of the surgical site. RESULTS: The mean age of patients treated with the open and MEDS approaches were 55.2 and 66.4 years, respectively (P=0.07). Paraspinal muscle CSA decreased by an average of 5.4% (SD=10.6%; range, -24.5% to +7.7%) in patients treated with the open approach and increased by an average of 9.9% (SD=14.4%; range, -9.8% to +33.1%) in patients treated with MEDS (P=0.02). For the open approach, changes in CSA did not differ significantly between the left and right sides for erector spinae (P=0.35) or multifidus muscles (P=0.90). After the MEDS approach there were no significant differences between the dilated and contralateral sides with regard to change in CSA for erector spinae (P=0.85) or multifidus muscles (P=0.95). CONCLUSIONS: Compared with the open approach for lumbar stenosis, MEDS had significantly less negative impact on the paraspinal muscle CSA. Previous reports have documented negative effects of paraspinal muscle injury, including weakness, disability, and pain. Collectively, these data suggest that the MEDS approach for lumbar decompression is less destructive to the paraspinous muscles than the open approach and may facilitate better clinical outcomes.

Zoledronic Acid Treatment After Acute Spinal Cord Injury: Results of a Randomized, Placebo-Controlled Pilot Trial.

OBJECTIVE: To determine the effect of intravenous zoledronic acid 5 mg on the extent and course of bone loss after spinal cord injury (SCI). DESIGN: Double-blind, randomized, placebo-controlled parallel-group trial. SETTING: Acute in-patient, tertiary-care rehabilitation hospital. PARTICIPANTS: Convenience sample of 17 in-patients with SCI <12 weeks before randomization; American Spinal Injury Association Impairment scale A, B, or C and medically stable. Twelve patients were evaluated at the primary endpoint at 6 months. METHODS: Patients meeting study criteria were randomly assigned to zoledronic acid 5 mg or matching placebo. Dual x-ray absorptiometry scan and serum for bone markers (type 1 procollagen amino-terminal propeptide, bone-specific alkaline phosphatase, collagen type 1 cross-linked C-telopeptide) were obtained at baseline and after 3 months, 6 months, and the every 6 months for up to 2 years. MAIN OUTCOME MEASURES: The primary endpoint was change in bone mineral density (BMD) at the total hip after 6 months; secondary endpoints were changes in BMD at other skeletal sites and changes in levels of serum bone markers. RESULTS: The group treated with zoledronic acid had a smaller decrease in BMD at 6 months at the total hip than the placebo group (right: -2.2 ± 3.4% versus -8.6 ± 3.5%, respectively, P = .03; left: -3.7 ± 1.0% versus -12.3 ± 6.9%, P = .03). Differences in BMD at the femoral neck were similar (right: -5.1 ± 6.5% versus -20.0 ± 6.4%, P = .01; left: -1.1 ± 3.5% versus -11.1 ± 7.4%, P = .02) with larger bone loss and smaller between group differences at the knee. Zoledronic acid resulted in a decrease in serum levels of both formation and resorption markers. CONCLUSIONS: Zoledronic acid is effective at mitigating bone loss after SCI. Duration of efficacy and activity at different skeletal sites may differ from that observed in able-bodied individuals and needs further study.

Reduction in Torsional Stiffness and Strength at the Proximal Tibia as a Function of Time Since Spinal Cord Injury.

Spinal cord injury (SCI) is characterized by marked bone loss and a high rate of low-energy fracture around regions of the knee. Changes in the mechanical integrity of bone after SCI are poorly defined, and a better understanding may inform approaches to prevent fractures. The purpose of this study was to quantify reductions in torsional stiffness and strength at the proximal tibia as a function of time since SCI. Sixty adults with SCI ranging from 0 to 50 years of duration and a reference group of 10 able-bodied controls received a CT scan of the proximal tibia. Measures of integral bone mineral were calculated for the total proximal tibia, and localized measures of cortical and trabecular bone mineral were calculated for the epiphysis, metaphysis, and diaphysis. Torsional stiffness (K) and strength (T(ult)) for the total proximal tibia were quantified using validated subject-specific finite element models. Total proximal tibia measures of integral bone mineral, K, and T(ult) decreased exponentially (r(2) = 0.52 to 0.70) and reached a new steady state within 2.1 to 2.7 years after SCI. Whereas new steady-state values for integral bone mineral and K were 52% to 56% (p < 0.001) lower than the reference group, the new steady state for T(ult) was 69% (p < 0.001) lower than the reference group. Reductions in total proximal tibia measures occurred through a combination of trabecular and endocortical resorption, leaving a bone comprised primarily of marrow fat rather than hydroxyapatite. These findings illustrate that a short therapeutic window exists early (ie, 2 years) after SCI, during which bone-specific intervention may attenuate reductions in mechanical integrity and ultimately prevent SCI-related fragility fracture.

The effect of call on neurosurgery residents' skills: implications for policy regarding resident call periods.

OBJECT: Although fatigue and its effects on surgical proficiency have been an actively researched area, previous studies have not examined the effect of fatigue on neurosurgery residents specifically. This study aims to quantify the effect of fatigue on the psychomotor and cognitive skills of neurosurgery residents. METHODS: Seven neurosurgery residents performed a minimum of 3 and a maximum of 4 sessions of 6 surgical exercises precall and postcall. The simulation exercises were designed to measure a surgeon's cognitive abilities, such as memory and attention, while performing simulated surgical tasks and exercises that have been previously validated in several studies, including studies measuring the impact of fatigue on general surgery residents. Each exercise measured tool-movement smoothness, time elapsed, and cognitive errors. The change in surgical skills in precall and postcall conditions was assessed by means of an ANOVA, with p < 0.05 considered statistically significant. RESULTS: The neurosurgery residents did not show a statistically significant difference in their surgical skills between the pre- and postcall states (p < 0.3, p < 0.4, and p < 0.2 for movement smoothness, time elapsed, and cognitive errors, respectively). The mean decrement for all residents in the postcall condition was 13.1%. CONCLUSIONS: Postcall fatigue is associated with a marginal decrease in proficiency during simulated surgery in neurosurgery residents. In a similar study, general surgery residents showed a statistically significant decrement of 27.3% in the postcall condition. The impact of fatigue on different specialties should be further investigated prior to implementation of a national physician work-hour policy.

Oculomotor function in chronic traumatic brain injury.

OBJECTIVE: To characterize oculomotor function using visually guided saccade and antisaccade (AS) tasks in chronic traumatic brain injury (TBI) and assess the relationship to neuropsychologic testing. BACKGROUND: TBI causes dysfunction of prefrontal cortex, in part by disrupting cortical and subcortical pathways, resulting in specific cognitive impairments. Oculomotor function tests provide a method of assessing the integrity of these pathways. METHODS: Twenty mild TBI (MTBI), 17 moderate to severe TBI (M/STBI), and 19 healthy controls underwent oculomotor and neuropsychologic testing. RESULTS: On the visually guided saccade task, the M/STBI showed longer latencies and reduced accuracy. On the AS task, which is more dependent on prefrontal cortex function, both patient groups committed more prosaccade errors than controls. On neuropsychologic testing, only the M/STBI patients were significantly impaired. Correlations were found between AS and neuropsychologic performance. CONCLUSIONS: The M/STBI group was impaired on both oculomotor tasks and neuropsychologic testing, consistent with more global neuropathology. The MTBI group showed impaired performance primarily on the AS task, consistent with prefrontal system dysfunction. Hence, oculomotor testing is sensitive to the range of neuropathology in chronic TBI, and importantly, may be more sensitive to neuropathology in MTBI.