Acute Lower Extremity Fracture Management in Chronic Spinal Cord Injury: 2022 Delphi Consensus Recommendations.

Our objective was to develop a clinical practice guideline (CPG) for the treatment of acute lower extremity fractures in persons with a chronic spinal cord injury (SCI). Methods: Information from a previous systematic review that addressed lower extremity fracture care in persons with an SCI as well as information from interviews of physical and occupational therapists, searches of the literature, and expert opinion were used to develop this CPG. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to determine the quality of evidence and the strength of the recommendations. An overall GRADE quality rating was applied to the evidence. Conclusions: Individuals with a chronic SCI who sustain an acute lower extremity fracture should be provided with education regarding the risks and benefits of operative and nonoperative management, and shared decision-making for acute fracture management should be used. Nonoperative management historically has been the default preference; however, with the advent of greater patient independence, improved surgical techniques, and advanced therapeutics and rehabilitation, increased use of surgical management should be considered. Physical therapists, kinesiotherapists, and/or occupational therapists should assess equipment needs, skills training, and caregiver assistance due to changes in mobility resulting from a lower extremity fracture. Therapists should be involved in fracture management as soon as possible following fracture identification. Pressure injuries, compartment syndrome, heterotopic ossification, nonunion, malunion, thromboembolism, pain, and autonomic dysreflexia are fracture-related complications that clinicians caring for patients who have an SCI and a lower extremity fracture may encounter. Strategies for their treatment are discussed. The underlying goal is to return the patient as closely as possible to their pre-fracture functional level with operative or nonoperative management.

Functional electrical stimulation (FES)-assisted rowing combined with zoledronic acid, but not alone, preserves distal femur strength and stiffness in people with chronic spinal cord injury.

We investigated the effect of 12 months of functional electrical stimulation-assisted rowing with and without zoledronic acid (ZA) on computationally estimated bone strength and stiffness in individuals with spinal cord injury. We found that rowing with ZA, but not rowing alone, improved stiffness at the distal femur, but not the proximal tibia. INTRODUCTION: People with spinal cord injury (SCI) have high fracture risk at the knee after the injury. Therapies that prevent bone loss or stimulate an anabolic response in bone have been proposed to reduce fractures. Zoledronic acid (ZA) is a potent bisphosphonate that inhibits osteoclastic resorption. Functional electrical stimulation (FES)-assisted rowing is a potentially osteogenic exercise involving mechanical stimulation to the lower extremities. Here, we investigated the effect of FES-assisted rowing with and without ZA on bone strength and stiffness in individuals with SCI. METHODS: Twenty individuals from a cohort of adults with SCI who participated in a clinical trial were included in the study. CT scans of their knees before and after the intervention were converted to finite element models. Bone failure strength (Tult) and stiffness were calculated at the proximal tibia and distal femur. RESULTS: Tult at the distal femur increased 4.6% among people who received rowing + ZA and decreased 13.9% among those with rowing only (p < 0.05 for group). Torsional and compressive stiffness at the femur metaphysis increased in people with rowing + ZA (+ 3 to +4%) and decreased in people with rowing only (- 7 to -8%; p < 0.05). Tult in the proximal tibia decreased in everyone, but the loss was attenuated in the rowing + ZA group. People with initially stronger bone tended to lose more strength. CONCLUSION: Overall, we observed increases in bone strength at the distal femur but not the proximal tibia, with FES-assisted rowing combined with ZA treatment. Rowing alone did not significantly prevent bone loss at either site, which might be attributed to insufficient mechanical loading.

Combination Therapy With Zoledronic Acid and FES-Row Training Mitigates Bone Loss in Paralyzed Legs: Results of a Randomized Comparative Clinical Trial.

Spinal cord injury (SCI) results in rapid, severe osteoporosis and an increased risk of lower extremity fractures. Despite the medical complications associated with these fractures, there is no standard of care to prevent osteoporotic fractures following SCI. Functional electrical stimulation- (FES-) assisted rowing is a promising intervention to improve bone health in SCI because of its ability to generate a muscular contraction in conjunction with mechanical loading of the lower extremity long bones. Combination therapy consisting of FES-rowing plus zoledronic acid (ZA) may be a superior treatment via inhibition of bone resorption and stimulation of new bone formation. We studied participants enrolled in a randomized clinical trial comparing FES-rowing alone with FES-rowing plus ZA to improve bone health in SCI. Volumetric CT scans at the distal femur and proximal tibial metaphyses were performed. Bone geometric properties (cortical thickness index [CTI], cortical compressive strength index [CSI], buckling ratio [BR], bending strength index) and mineral (cortical bone volume [CBV], cortical bone mineral density, cortical bone mineral content) indices were determined. In models adjusting for baseline values, we found that the CBV (p = 0.05 to 0.006), the CTI (p = 0.009), and the BR (p = 0.001) at both the distal femoral and proximal tibial metaphyses were greater in the ZA plus rowing group compared with the rowing-only group. Similarly, there was a significant positive association between the total rowing work completed and the BR at the proximal tibia (p = 0.05). A subgroup analysis of the rowing-only arm showed that gains in the CSI at the tibial metaphysis varied in a dose-dependent fashion based on the total amount of exercise performed (p = 0.009). These findings demonstrate that the osteogenic response to FES-rowing is dose-dependent. Combination therapy with ZA and FES-row training has therapeutic potential to improve bone quality, and perhaps reduce fracture risk at the most common fracture site following SCI. © 2019 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Anthropometric and biomechanical characteristics of body segments in persons with spinal cord injury.

People with spinal cord injury (SCI) experience bone and muscle loss in their paralyzed limbs that is most rapid and severe in the first 3years after injury. Restoration of mechanical loading through therapeutic physical activity may potentially slow or reverse post-SCI bone loss, however, therapeutic targets cannot be developed without accurate biomechanical models. Obesity is prevalent among SCI population, and it alters body composition and further affects parameters of these models. Here, clinical whole body dual-energy X-ray absorptiometry data from people with acute (n=39) and chronic (n=61) SCI were analyzed to obtain anthropometric parameters including segment masses, center of mass location, and radius of gyration for both obese and non-obese individuals. Chronic SCI was associated with higher normalized trunk mass of 3.2%BW and smaller normalized leg mass of 1.8%BW in males, but no significant changes in segment centers of mass or radius of gyration. People with chronic SCI had 58.6% lean mass in the trunk, compared to 66.6% lean mass in those with acute SCI (p=0.01), with significant changes in all segments. Obesity was associated with an increase in trunk mass proportion of 3.1%BW, proximal shifts in thigh and upper arm center of mass, and changes to thigh and shank radius of gyration. The data presented here can be used to accurately represent the anthropometrics of SCI population in biomechanical studies, considering obesity and injury duration.

Wheelchair use and lipophilic statin medications may influence bone loss in chronic spinal cord injury: findings from the FRASCI-bone loss study.

We identified a protective bone effect at the knee with lipophilic statin use in individuals with chronic spinal cord injury. Lipophilic statin users gained bone at the knee compared to non-users and wheelchair users lost bone compared to walkers. Ambulation and or statins may be effective osteogenic interventions in chronic spinal cord injury (SCI). INTRODUCTION: SCI increases the risk of osteoporosis and low-impact fractures, particularly at the knee. However, during the chronic phase of SCI, the natural history and factors associated with longitudinal change in bone density remain poorly characterized. In this study, we prospectively assessed factors associated with change in bone density over a mean of 21 months in 152 men and women with chronic SCI. METHODS: A mixed model procedure with repeated measures was used to assess predictors of change in bone mineral density (PROC MIXED) at the distal femur and proximal tibia. Factors with a p value of <0.10 in the univariate mixed models, as well as factors that were deemed clinically significant (gender, age, and walking status), were assessed in multivariable models. Factors with a p value of ≤0.05 were included in the final model. RESULTS: We found no association between bone loss and traditional osteoporosis risk factors, including age, gender, body composition, or vitamin D level or status (normal or deficient). In both crude and fully adjusted models, wheelchair users lost bone compared to walkers. Similarly, statin users gained bone compared to nonusers. CONCLUSIONS: The statin finding is supported by reports in the general population where statin use has been associated with a reduction in bone loss and fracture risk. Our results suggest that both walking and statins may be effective osteogenic therapies to mitigate bone loss and prevent osteoporosis in chronic SCI. Our findings also suggest that loss of mechanical loading and/or neuronal factors contribute more to disuse osteoporosis than traditional osteoporosis risk factors.

Adiponectin is associated with bone strength and fracture history in paralyzed men with spinal cord injury.

UNLABELLED: We explored the association between adiponectin levels and bone strength in paralyzed men with spinal cord injury. We found that bone strength was inversely associated with circulating adiponectin levels. Thus, strength estimates and adiponectin levels may improve fracture risk prediction and detection of response to osteogenic therapies following spinal cord injury. PURPOSE: Previous research has demonstrated an inverse relationship between circulating adiponectin and bone mineral density, suggesting that adiponectin may be used as a biomarker for bone health. However, this relationship may reflect indirect effects on bone metabolism via adipose-mediated mechanical pathways rather than the direct effects of adipokines on bone metabolism. Thus, we explored the association between circulating adiponectin levels and bone strength in 27 men with spinal cord injury. METHODS: Plasma adiponectin levels were quantified by ELISA assay. Axial stiffness and maximal load to fracture of the distal femur were quantified via finite element analysis using reconstructed 3D models of volumetric CT scans. We also collected information on timing, location, and cause of previous fractures. RESULTS: Axial stiffness and maximal load were inversely associated with circulating adiponectin levels (R (2) = 0.44, p = 0.01; R (2) = 0.58, p = 0.05) after adjusting for injury duration and lower extremity lean mass. In individuals with post-SCI osteoporotic fractures, distal femur stiffness (p = 0.01) and maximal load (p = 0.005) were lower, and adiponectin was higher (p = 0.04) than those with no fracture history. CONCLUSIONS: Based on these findings, strength estimates may improve fracture risk prediction and detection of response to osteogenic therapies following spinal cord injury. Furthermore, our findings suggest that circulating adiponectin may indeed be a feasible biomarker for bone health and osteoporotic fracture risk in paralyzed individuals with spinal cord injury.

Sclerostin: a candidate biomarker of SCI-induced osteoporosis.

UNLABELLED: We assessed several circulating proteins as candidate biomarkers of bone status in men with chronic spinal cord injury. We report that sclerostin is significantly associated with bone mineral content and bone density at all skeletal sites tested. We found no association between bone and any other tested biomarker. INTRODUCTION: Spinal cord injury results in severe osteoporosis. To date, no circulating biomarker of spinal cord injury (SCI)-induced osteoporosis has been identified. We recently reported that circulating sclerostin is associated with bone density in chronic SCI. In this study, we assessed several circulating proteins as candidate biomarkers of bone in men with chronic SCI. METHODS: We assessed the relationship between bone mineral content or bone density and the following circulating bone-related proteins: sclerostin, DKK-1, soluble receptor activator of nuclear factor kappa B ligand, osteoprotegerin, osteocalcin, and c-telopeptide in 39 men with chronic SCI and 10 men with no SCI. RESULTS: After adjusting for age, lower sclerostin levels were significantly associated with lower bone mineral content and bone density at all skeletal sites tested (p = 0.0002-0.03). No other circulating protein was associated with bone mineral content or bone mineral density (p = 0.18-0.99). CONCLUSION: These findings suggest that circulating sclerostin reflects the severity of bone loss and is a candidate biomarker of osteoporosis severity in chronic SCI.

SNX10 is required for osteoclast formation and resorption activity.

RANKL-stimulation of osteoclast precursors results in up-regulation of genes involved in the process of differentiation and activation. In this report we describe the expression and functional characterization of Sorting Nexin 10 (snx10). Snx10 belongs to the sorting nexin (SNX) family, a diverse group of proteins with a common feature: the PX domain, which is involved in membrane trafficking and cargo sorting in endosomes. Snx10 is strongly up-regulated during RANKL-induced osteoclast differentiation in vitro and expressed in osteoclasts in vivo. qPCR analysis confirmed a significant increase in the expression of snx10 in in vitro-derived osteoclasts, as well as in femur and calvaria. Immunohistochemical analysis of mouse embryo sections showed expression in long bone, calvariae, and developing teeth. The expression was limited to cells that also expressed TRAP, demonstrating osteoclastic localization. Confocal immunofluorescence and subcellular fractionation analysis revealed Snx10 localization in the nucleus and in the endoplasmic reticulum (ER). To study a possible role for snx10 in osteoclast differentiation and function we silenced snx10 expression and found that snx10 silencing inhibited RANKL-induced osteoclast formation and osteoclast resorption on hydroxyapatite. Silencing also inhibited TRAP secretion. Taken together, these results confirm that snx10 is expressed in osteoclasts and is required for osteoclast differentiation and activity in vitro. Since inhibition of vesicular trafficking is essential for osteoclast formation and activity and SNX10 is involved in intracellular vesicular trafficking, these studies may identify a new candidate gene involved in the development of human bone diseases including osteoporosis.

Osteoporotic fractures and hospitalization risk in chronic spinal cord injury.

UNLABELLED: Osteoporosis is a well acknowledged complication of spinal cord injury. We report that motor complete spinal cord injury and post-injury alcohol consumption are risk factors for hospitalization for fracture treatment. The clinical assessment did not include osteoporosis diagnosis and treatment considerations, indicating a need for improved clinical protocols. INTRODUCTION: Treatment of osteoporotic long bone fractures often results in lengthy hospitalizations for individuals with spinal cord injury. Clinical features and factors that contribute to hospitalization risk have not previously been described. METHODS: Three hundred and fifteen veterans > or = 1 year after spinal cord injury completed a health questionnaire and underwent clinical exam at study entry. Multivariate Cox regression accounting for repeated events was used to assess longitudinal predictors of fracture-related hospitalizations in Veterans Affairs Medical Centers 1996-2003. RESULTS: One thousand four hundred and eighty-seven hospital admissions occurred among 315 participants, and 39 hospitalizations (2.6%) were for fracture treatment. Median length of stay was 35 days. Fracture-related complications occurred in 53%. Independent risk factors for admission were motor complete versus motor incomplete spinal cord injury (hazard ratio = 3.73, 95% CI = 1.46-10.50). There was a significant linear trend in risk with greater alcohol consumption after injury. Record review indicated that evaluation for osteoporosis was not obtained during these admissions. CONCLUSIONS: Assessed prospectively, hospitalization in Veterans Affairs Medical Centers for low-impact fractures is more common in motor complete spinal cord injury and is associated with greater alcohol use after injury. Osteoporosis diagnosis and treatment considerations were not part of a clinical assessment, indicating the need for improved protocols that might prevent low-impact fractures and related admissions.

Age and motor score predict osteoprotegerin level in chronic spinal cord injury.

OBJECTIVE: Individuals with spinal cord injury (SCI) develop a severe form of osteoporosis below the level of injury that is poorly understood. We conducted a preliminary investigation to assess whether circulating markers of bone turnover and circulating RANKL/OPG levels are related to the severity of SCI, aging, or to differences in mobility (i.e., walking or using a wheelchair). METHODS: Sixty-four caucasian men >or=1.6 years since injury selected based on locomotive mode provided blood samples and completed a health questionnaire at the VA Boston Healthcare System from 10/2003 to 6/2005. Plasma sRANKL, osteoprotegerin (OPG), osteocalcin and carboxyterminal telopeptide of type I collagen (CTx) levels were determined. RESULTS: Increasing age was significantly associated with increased OPG and CTx. Injury severity was predictive of OPG levels, and adjusting for age, participants with cervical motor complete and ASIA C SCI (n=11) had significantly lower mean OPG (46.1 pg/ml) levels than others (63.4 pg/ml). Locomotive mode was not associated with differences in bone markers. CONCLUSIONS: Severe cervical spinal cord injury is associated with decreased circulating OPG levels placing these patients at risk for accelerated bone loss that appears unrelated to locomotive mode.

NHA-oc/NHA2: a mitochondrial cation-proton antiporter selectively expressed in osteoclasts.

Bone resorption is regulated by a complex system of hormones and cytokines that cause osteoblasts/stromal cells and lymphocytes to produce factors including RANKL, that ultimately result in the differentiation and activation of osteoclasts, the bone resorbing cells. We used a microarray approach to identify genes upregulated in RANKL-stimulated osteoclast precursor cells. Osteoclast expression was confirmed by multiple tissue Northern and in situ hybridization analysis. Gene function studies were carried out by siRNA analysis. We identified a novel gene, which we termed nha-oc/NHA2, which is strongly upregulated during RANKL-induced osteoclast differentiation in vitro and in vivo. nha-oc/NHA2 encodes a novel cation-proton antiporter (CPA) and is the mouse orthologue of a human gene identified in a database search: HsNHA2. nha-oc/NHA2 is selectively expressed in osteoclasts. NHA-oc/NHA2 protein localizes to the mitochondria, where it mediates Na(+)-dependent changes in mitochondrial pH and Na(+) acetate induced mitochondrial passive swelling. RNA silencing of nha-oc/nha2 reduces osteoclast differentiation and resorption, suggesting a role for NHA-oc/NHA2 in these processes. nha-oc/NHA2 therefore is a novel member of the CPA family and is the first mitochondrial NHA characterized to date. nha-oc/NHA2 is also unique in that it is the first eukaryotic and tissue-specific CPA2 characterized to date. NHA-oc/NHA2 displays the expected activities of a bona fide CPA and plays a key role(s) in normal osteoclast differentiation and function.

Rapid estimation of biochemical oxygen demand.

The feasibility of using columnar reactors containing immobilized microorganisms for the rapid estimation of BOD was demonstrated in this study. Dilutions of three types of industrial effluents were tested by the BOD5 test and by this experimental system. A high degree of correlation (r = 0.98) was observed between results of the two tests. The mean standard error of estimation of the experimental system was 11%.