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.

Laboratory evaluation of secondary causes of bone loss in Veterans with spinal cord injury and disorders.

An electronic health record (eHR) review of Veterans with a spinal cord injury and disorder (SCI/D) was conducted to understand the extent to which Veterans Affairs (VA) providers pursue workups for secondary causes of osteoporosis in this population. Laboratory tests for secondary causes were ordered in only one-third of Veterans, with secondary causes identified in two-thirds of those tested, most frequently, hypogonadism and hypovitaminosis D. PURPOSE: To identify workups for secondary causes of osteoporosis in SCI/D and the extent to which subspecialty consultations are sought. METHODS: A total of 3018 prescriptions for an osteoporosis medication (bisphosphonate, calcitonin, denosumab, raloxifene, teriparatide) among 2675 Veterans were identified in fiscal years 2005-2015 from VA administrative databases. Approximately 10% of these prescriptions were selected for eHR review. RESULTS: eHR records of 187 Veterans with a SCI/D who had received pharmacological treatment for osteoporosis were reviewed. Workups for secondary causes of osteoporosis were performed in 31.5% of Veterans (n = 59) with approximately 64.4% of those tested (n = 38) having at least one abnormality. Hypogonadism (52.0% of those tested) and hypovitaminosis D (50.0% of those tested) were the most common secondary causes of osteoporosis identified in this population. Approximately 10% of primary care and SCI providers consulted subspecialists for further evaluation and treatment of osteoporosis. Endocrinologists more frequently performed a workup for secondary causes of osteoporosis compared to other provider specialties. CONCLUSIONS: Screening for secondary causes of osteoporosis, particularly for hypogonadism and hypovitaminosis D, should be considered in patients with a SCI/D.

The renin-angiotensin aldosterone system and osteoporosis: findings from the Women's Health Initiative.

New users of RAAS inhibitors, including ACE inhibitors and ARBs, have a small increased risk for fracture in the first 3 years of use, with a reduced risk of fracture with longer duration of use. INTRODUCTION: Pharmacological inhibitors of the renin-angiotensin aldosterone system (RAAS) are used to treat hypertension. However, the relationship of these medications to osteoporosis is inconsistent, and no study has included simultaneous measurements of both incident fractures and bone mineral density (BMD). METHODS: The association of RAAS inhibitor use (n = 131,793) with incident fractures in new users of these medications in women in the Women's Health Initiative over a minimum median follow-up of 6.5 years was assessed by Cox proportional hazard models. The association of incident fractures by a cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated. Subgroup analysis of fracture risk by RAAS inhibitor use confined to women with hypertension was also performed (n = 33,820). The association of RAAS inhibitor use with changes in BMD of the hip was estimated by linear regression in 8940 women with dual energy X-ray absorptiometry measurements. RESULTS: There was no significant association between RAAS inhibitor use and all fractures in the final adjusted multivariable models including hip BMD (HR 0.86 (0.59, 1.24)). However, among users of RAAS inhibitors, including ACE inhibitors and angiotensin receptor blockers (ARBs), hazard ratios for all incident fracture sites in final multivariable models including hip BMD showed dramatic differences by duration of use, with short duration of use (3 years or less) associated with a marked increased risk for fracture (HR 3.28 (1.66, 6.48)) to (HR 6.23 (3.11, 12.46)) and use for more than 3 years associated with a reduced fracture risk (HR 0.40 (0.24, 0.68) to (HR 0.44 (0.20, 0.97)) . Findings were similar in the subgroup of women with a history of hypertension. There was no significant change in BMD of the hip by RAAS inhibitor use. CONCLUSIONS: In postmenopausal women, use of RAAS inhibitors, including ACE inhibitors and ARBs, is associated with an increased risk for fracture among new users of these medications in the first 3 years of use. However, long-term use (> 3 years) is associated with a reduced risk. Consideration for fracture risk may be part of the decision-making process for initiation of these medications for other disease states.

Association of DPP-4 activity with BMD, body composition, and incident hip fracture: the Cardiovascular Health Study.

There was no association of plasma DPP-4 activity levels with bone mineral density (BMD), body composition, or incident hip fractures in a cohort of elderly community-dwelling adults. INTRODUCTION: Dipeptidyl peptidase IV (DPP-4) inactivates several key hormones including those that stimulate postprandial insulin secretion, and DPP-4 inhibitors (gliptins) are approved to treat diabetes. While DPP-4 is known to modulate osteogenesis, the relationship between DPP-4 activity and skeletal health is uncertain. The purpose of the present study was to examine possible associations between DPP-4 activity in elderly subjects enrolled in the Cardiovascular Health Study (CHS) and BMD, body composition measurements, and incident hip fractures. METHODS: All 1536 male and female CHS participants who had evaluable DXA scans and plasma for DPP-4 activity were included in the analyses. The association between (1) BMD of the total hip, femoral neck, lumbar spine, and total body; (2) body composition measurements (% lean, % fat, and total body mass); and (3) incident hip fractures and plasma levels of DPP-4 activity were determined. RESULTS: Mean plasma levels of DPP-4 activity were significantly higher in blacks (227 ± 78) compared with whites (216 ± 89) (p = 0.04). However, there was no significant association of DPP-4 activity with age or gender (p ≥ 0.14 for both). In multivariable adjusted models, there was no association of plasma DPP-4 activity with BMD overall (p ≥ 0.55 for all) or in gender stratified analyses (p ≥ 0.23). There was also no association of DPP-4 levels and incident hip fractures overall (p ≥ 0.24) or in gender stratified analyses (p ≥ 0.39). CONCLUSION: Plasma DPP-4 activity, within the endogenous physiological range, was significantly associated with race, but not with BMD, body composition, or incident hip fractures in elderly community-dwelling subjects.

Dual-energy X-ray absorptiometry and fracture prediction in patients with spinal cord injuries and disorders.

Low T-scores at the hip predict incident fractures in persons with a SCI. INTRODUCTION: Persons with a spinal cord injury (SCI) have substantial morbidity and mortality following osteoporotic fractures. The objective of this study was to determine whether dual-energy X-ray absorptiometry (DXA) measurements predict osteoporotic fractures in this population. METHODS: A retrospective historical analysis that includes patients (n = 552) with a SCI of at least 2 years duration who had a DXA performed and were in the VA Spinal Cord Disorders Registry from fiscal year (FY) 2002-2012 was performed. RESULTS: The majority of persons (n = 455, 82%) had a diagnosis of osteoporosis or osteopenia, with almost half having osteoporosis. BMD and T-scores at the lumbar spine were not significantly associated with osteoporotic fractures (p > 0.48) for both. In multivariable analyses, osteopenia (OR = 4.75 95% CI 1.23-17.64) or osteoporosis (OR = 4.31, 95% CI 1.15-16.23) compared with normal BMD was significantly associated with fractures and higher T-scores at the hip were inversely associated with fractures (OR 0.73 (95% CI 0.57-0.92)). There was no significant association of T-scores or World Health Organization (WHO) classification with incident fractures in those with complete SCI (p > 0.15 for both). CONCLUSION: The majority (over 80%) of individuals with a SCI have osteopenia or osteoporosis. DXA-derived measurements at the hip, but not the lumbar spine, predict fracture risk in persons with a SCI. WHO-derived bone density categories may be useful in classifying fracture risk in persons with a SCI.

Risk factors for osteoporotic fractures in persons with spinal cord injuries and disorders.

UNLABELLED: Clinical risk factors for fracture were explored among Veterans with a spinal cord injury. At the end of 11 years of follow-up, the absolute risk of fracture was approximately 20 %. Among the clinical and SCI-related factors explored, a prior history of fracture was strongly associated with incident fracture. INTRODUCTION: Few studies to date have comprehensively addressed clinical risk factors for fracture in persons with spinal cord injury (SCI). The purpose of this study was to identify risk factors for incident osteoporotic fractures in persons with a SCI that can be easily determined at the point of care. METHODS: The Veteran's Affairs Spinal Cord Dysfunction Registry, a national database of persons with a SCI, was used to examine clinical and SCI-related risk factors for fracture. Incident fractures were identified in a cohort of persons with chronic SCI, defined as SCI present for at least 2 years. Cox regression models were used to estimate the risk of incident fractures. RESULTS: There were 22,516 persons with chronic SCI included in the cohort with 3365 incident fractures. The mean observational follow-up time for the overall sample was 6.2 years (median 6.0, IQR 2.9-11.0). The mean observational follow-up time for the fracture group was 3.9 years (median 3.3, IQR 1.4-6.1) and 6.7 years (median 6.7, IQR 3.1-11.0) for the nonfracture group. By the end of the study, which included predominantly older Veterans with a SCI observed for a relatively short period of time, the absolute (i.e., cumulative hazard) for incident fractures was 0.17 (95%CI 0.14-0.21). In multivariable analysis, factors associated with an increased risk of fracture included White race, traumatic etiology of SCI, paraplegia, complete extent of SCI, longer duration of SCI, use of anticonvulsants and opioids, prevalent fractures, and higher Charlson Comorbidity Indices. Women aged 50 and older were also at higher risk of sustaining an incident fracture at any time during the 11-year follow-up period. CONCLUSIONS: There are multiple clinical and SCI-related risk factors which can be used to predict fracture in persons with a SCI. Clinicians should be particularly concerned about incident fracture risk in persons with a SCI who have had a previous fracture.

Soluble CD14 and fracture risk.

UNLABELLED: Soluble CD14 (sCD14) is an inflammatory marker associated with osteoclasts. Using Cox proportional hazards models, we found a positive association between plasma levels of sCD14 and risk of incident fracture among participants in the Cardiovascular Health Study. sCD14 may be useful in identifying those at risk for fracture. INTRODUCTION: Soluble CD14, a proinflammatory cytokine, is primarily derived from macrophages/monocytes that can differentiate into osteoclasts. The purpose of this study was to examine the relationship between sCD14 levels and osteoporotic fractures. METHODS: In the Cardiovascular Health Study, 5462 men and women had sCD14 levels measured at baseline. Incident hip fractures (median follow-up time 12.5 years) and incident composite fractures (defined as the first hip, pelvis, humerus, or distal radius fracture, median follow-up 8.6 years) were identified from hospital discharge summaries and/or Medicare claims data. Cox proportional hazards models were used to model the association between sCD14 levels and time to incident hip or composite fracture, overall and as a function of race and gender. RESULTS: In unadjusted models, there was a positive association between sCD14 levels (per 1 standard deviation increase, i.e., 361.6 ng/mL) and incident hip (HR, 1.26; 95 % CI, 1.17, 1.36) and composite (HR, 1.20; 95 % CI, 1.12, 1.28) fractures. When models were fully adjusted for demographics, lifestyle factors, and medication use, these associations were no longer significant. However, in whites, the association of sCD14 levels with hip fractures remained significant in fully adjusted models (HR, 1.11; 95 % CI, 1.01-1.23). Associations of sCD14 levels with hip and composite fracture did not differ between men and women. CONCLUSIONS: In this large cohort of community-dwelling older adults, higher sCD14 levels were associated with an increased risk of incident hip fractures in whites.

Surgical compared with nonsurgical management of fractures in male veterans with chronic spinal cord injury.

STUDY DESIGN: Retrospective review of a clinical database. OBJECTIVES: To examine treatment modalities of incident appendicular fractures in men with chronic SCI and mortality outcomes by treatment modality. SETTING: United States Veterans Health Administration Healthcare System. METHODS: This was an observational study of 1979 incident fractures that occurred over 6 years among 12 162 male veterans with traumatic SCI of at least 2 years duration from the Veterans Health Administration (VA) Spinal Cord Dysfunction Registry. Treatment modalities were classified as surgical or nonsurgical treatment. Mortality outcomes at 1 year following the incident fracture were determined by treatment modality. RESULTS: A total of 1281 male veterans with 1979 incident fractures met inclusion criteria for the study. These fractures included 345 (17.4%) upper-extremity fractures and 1634 (82.6%) lower-extremity fractures. A minority of patients (9.4%) were treated with surgery. Amputations and disarticulations accounted for 19.7% of all surgeries (1.3% of all fractures), and the majority of these were done more than 6 weeks following the incident fracture. There were no significant differences in mortality among men with fractures treated surgically compared with those treated nonsurgically. CONCLUSIONS: Currently, the majority of appendicular fractures in male patients with chronic SCI are managed nonsurgically within the VA health-care system. There is no difference in mortality by type of treatment.

Morbidity following lower extremity fractures in men with spinal cord injury.

UNLABELLED: The Veterans Affairs Spinal Cord Dysfunction Registry from 2002 to 2007 was reviewed to determine whether men with spinal cord injury (SCI) and lower extremity fractures had an increased risk of complications compared to those without fractures. We determined that fractures are associated with significant consequences, particularly during the first month postfracture. INTRODUCTION: Despite increasing longevity, patients with SCI have a substantial number of illnesses and comorbid conditions. Lower extremity fractures are frequent events in these patients. However, whether these fractures are associated with any increased risk of complications in SCI is not certain. The purpose of this report was to determine the impact of lower extremity fractures on morbidities in men with SCI. METHODS: A population-based, nested, case-control (1,027 cases and 1,027 propensity-matched controls) of men enrolled in the Veterans Affairs Spinal Cord Dysfunction Registry from fiscal years 2002 to 2007 was reviewed to determine whether lower extremity fractures were associated with an increased risk for complications. RESULTS: In propensity score models matched for demographic (age, race) and SCI-related injury factors (level/completeness of SCI), Veterans Affairs-service connection status, and comorbidities, at 1 month following the fracture, there was an increased risk for respiratory infections, pressure ulcers, urinary tract infections, thromboembolic events, depression, and delirium (p ≤ 0.03 for all). Over 12 months, the only complication more common in fracture cases was pressure ulcers (p < 0.01), with an absolute difference of less than 2 % when compared to controls. There was no significant increased risk of cardiac arrhythmias at any time examined following fracture (≥0.12). CONCLUSIONS: Lower extremity fractures are associated with significant consequences in men with SCI during the first month postfracture, but they do not persist for a long term, except for pressure ulcers. Targeted interventions to prevent complications should be considered following lower extremity fractures in SCI, particularly in the first month following fracture.

Pamidronate infusion in patients with systemic sclerosis results in changes in blood mononuclear cell cytokine profiles.

A single infusion of pamidronate was given to patients with systemic sclerosis (scleroderma, SSc) to assess effects on cytokine production by peripheral blood mononuclear cells (PBMC) and lymphocyte subsets. Eighteen patients with SSc received a single intravenous dose of 60 mg of pamidronate and were followed for 6 months. Assessment of cytokine production [interferon (IFN)-gamma, interleukin (IL)-10, transforming growth factor (TGF)-beta1, tumour necrosis factor (TNF)-alpha and IL-4] by PBMC and lymphocyte subsets by flow cytometry was carried out before and after the pamidronate infusion. Unstimulated PBMC produced increased amounts of IFN-gamma and TNF-alpha and reduced levels of TGF-beta1 for up to 24 weeks after the infusion. gammadelta T cells from patients with SSc were activated in vitro and produced increased IFN-gamma. The effects of pamidronate on modulation of cytokine profiles in patients with SSc may merit future study.

Induction of immune tolerance to human type I collagen in patients with systemic sclerosis by oral administration of bovine type I collagen.

OBJECTIVE: To determine whether oral tolerance to type I collagen (CI) could be induced in patients with systemic sclerosis (SSc). METHODS: Twenty adult patients with limited or diffuse SSc were enrolled in a study to receive 0.1 mg of solubilized native bovine CI daily for 1 month, followed by 0.5 mg daily for 11 months. Peripheral blood mononuclear cells (PBMC) were obtained from the patients and cultured with human alpha1(I) and alpha2(I) chains, before and after CI treatment. Culture supernatants were analyzed for levels of interferon-gamma (IFNgamma) and interleukin-10 (IL-10). Sera obtained before and after treatment were analyzed for levels of soluble IL-2 receptor (sIL-2R). Although this study was not intended to assess the clinical efficacy of oral CI administration in SSc, selected measures of disease severity and organ involvement were evaluated. RESULTS: Oral administration of CI to SSc patients induced significant reductions in levels of IFNgamma and IL-10 in alpha1(I)- and alpha2(I)-stimulated PBMC culture supernatants, indicating that T cell immunity to CI was decreased by this treatment. Serum levels of sIL-2R also decreased significantly after oral CI treatment, suggesting a reduction in T cell activation. Significant improvements occurred in the modified Rodnan skin thickness score and the modified Health Assessment Questionnaire after 12 months of oral CI in this open trial. The lung carbon monoxide diffusing capacity improved statistically and showed a trend toward clinically significant improvement. CONCLUSION: Oral administration of bovine CI to patients with diffuse or limited SSc induces a reduction in T cell reactivity to human CI, appears to be well tolerated, and does not worsen the disease. Further evaluation of oral tolerance to CI in patients with SSc is justified to determine whether it has therapeutic efficacy.

Lack of efficacy of oral bovine type II collagen added to existing therapy in rheumatoid arthritis.

OBJECTIVE: To investigate the efficacy of oral type II collagen (CII) in the treatment of rheumatoid arthritis (RA), when added to existing therapy. METHODS: Patients with active RA (n = 190) were randomized into a 6-month, double-blind, placebo-controlled trial. Patients continued to take their current arthritis medications. Patients received either placebo or bovine CII, 0.1 mg/day for 1 month, then 0.5 mg/day for 5 months. RESULTS: There were no significant differences between the baseline characteristics of either group. The primary response parameter was the American College of Rheumatology (ACR) preliminary definition of improvement in RA (ACR 20). There was no statistically significant difference in the ACR 20 after 6 months (20.0% of placebo patients; 16.84% of bovine CII patients). There were significant differences in several clinical variables after treatment, all favoring the placebo group. CONCLUSION: Oral solubilized bovine CII, added to existing therapy, did not improve disease activity in patients with RA.

The role of collagen abnormalities in ultrasound and densitometry assessment: In vivo evidence.

There is little information concerning how the mutation of collagen affects bone mineralization and the assessment of bone properties. To estimate these influences, we performed ultrasonic assessments of the calcaneus and bone mineral density (BMD) measurements of the hip and lumbar spine. Females with diseases related to the mutation of collagen [Ehlers-Danlos syndrome (EDS) type III and systemic sclerosis (SSc)] participated in this study. We compared the broadband ultrasound attenuation (BUA and UBI-4), the average transit time through the heel (TTH), and a multiple factor index (UBI-4T) with control subjects matched on age, race, and menstrual status. Both groups of patients had BMD of the spine (L2-L4) within the normal range for their age and sex (for EDS: n = 23, 1.14 +/- 0. 14 g/cm2 and z-score = 0.37; for SSc: n = 15, 0.98 +/- 0.15 g/cm2 and z-score = 0.20). EDS and SSc subjects had lower BMD of the femoral neck (FN) compared with controls (for EDS: 0.91 +/- 0.13 g/cm2, z-score = -0.41, P = 0.025; for SSc 0.67 +/- 0.13 g/cm2, z-score = -0.92, P = 0.006). Subjects with EDS and SSc also had lower BUA values (P = 0.051-0.001) compared with controls. After adjusting for body weight, height, and the level of physical activity, the difference in FN BMD between EDS or SSc and controls became marginal (EDS: P = 0.072; SSc: P = 0.086). However, the significant difference for BUA between subjects and controls remained for EDS (P = 0.008), and disappeared for SSc (0.70) after adjusting for weight, height, level of physical activity, and BMD. These results suggest that the abnormalities of collagen may impact on bone mass measurements differently depending on skeletal site, modality of the assessment, and the source and nature of collagen defects. To determine whether collagen properties influence QUS, proper models in vivo and in vitro should be used.

Effects of long-term administration of methotrexate on bone mineral density in rheumatoid arthritis.

Because previous studies of high-dose methotrexate usage have demonstrated an effect on bone formation and resorption, this study was done to determine whether long-term, low-dose use of methotrexate for the treatment of rheumatoid arthritis causes bone loss. Bone mineral density (BMD) of the lumbar spine and hip was measured in 10 Caucasian postmenopausal women who had never received methotrexate and 10 Caucasian postmenopausal women who had received the drug for 3 or more years. There were no significant differences in BMD at the lumbar spine (L2-L4) between patients who had used long-term methotrexate compared with patients never treated with methotrexate (1.08 +/- 0.08 g/cm2 versus 0.98 +/- 0.14 g/cm2, respectively; P = 0.08). Similarly, there were no significant differences in BMD at the femoral neck between methotrexate users and nonusers (0.81 +/- 0.08 g/cm2 versus 0.76 +/- 0.15 g/cm2, respectively; P = 0.42). These results suggest that long-term low-dose methotrexate treatment for rheumatoid arthritis is not associated with accelerated bone loss.

Ultrasound measurements of the calcaneus: effects of ethnicity.

This study investigated whether there were differences in quantitative ultrasound (QUS) of the calcaneus between African-American and Caucasian females. QUS-1X, an ultrasonometer by Metra Biosystems Inc., was used to determine broadband ultrasound attenuation (UBI-4) using Burg Spectral Estimation in decibels/megahertz. The average transit time through the heel (TTH) in microseconds was used to estimate bone size. A multiple factor index taking into account bone size, UBI-4T, was calculated by dividing UBI-4 by TTH in decibels/(Megahertz x microseconds). Results showed that premenopausal Caucasian females (n = 37) have approx 6-8% lower values (p < 0.05) of QUS indices than their African-American (n = 54) counterparts. However, after adjusting for bone size, the differences in attenuation disappeared. Pilot data for males (Caucasian: n = 16, African-American: n = 18) suggest that the differences in QUS appear to be related to bone size. The limited scope of our study supports the fact that there are differences in QUS between premenopausal Caucasian and African-American females, but not with the same magnitude as evidenced by dual X-ray absorptiometry. We recommend that more data be collected on ethnic differences across all age ranges, to help understand how QUS may be used to assess bone mass and determine its value either as a screening tool to diagnose low bone mass or as a tool to predict osteoporotic fracture within various ethnic groups.

Osteoporosis of pregnancy: long-term follow-up of patients and their offspring.

BACKGROUND: The usual course of osteoporosis of pregnancy is complete resolution without recurrence. We report the 10-year follow-up of two patients with osteoporosis of pregnancy and their offspring. CASES: A 30-year-old woman presented with right hip pain at 30 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. A dual-energy x-ray absorptiometry performed on the 11-year-old daughter of this pregnancy showed osteopenia. A 26-year-old woman presented with left hip pain at 16 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. Dual-energy x-ray absorptiometry performed on the 13-year-old daughter of this pregnancy showed osteopenia. CONCLUSION: Osteoporosis of the hip discovered during pregnancy may not be a transient process and should prompt a search for osteopenia in both mother and offspring.