Epigenetic age biomarkers and risk assessment in adult spinal deformity: a novel association of biological age with frailty and disability.

OBJECTIVE: Surgery for spinal deformity has the potential to improve pain, disability, function, self-image, and mental health. These surgical procedures carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring the methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight onto the molecular basis of frailty and to improve current risk assessment tools. METHODS: Adult patients who underwent deformity surgery were prospectively enrolled. Preoperative whole blood samples were used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC)-based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both quantitative polymerase chain reaction (telomere to single gene [T/S] ratio) and a methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiologists Physical Status Classification System class, and scores on the Charlson Comorbidity Index, adult spinal deformity frailty index (ASD-FI), Edmonton Frail Scale (EFS), Oswestry Disability Index, and Scoliosis Research Society-22r questionnaire (SRS-22r). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and beta coefficients (ß) from linear regression, adjusted for BMI and sex, were calculated. RESULTS: Eighty-three patients were enrolled with a mean age of 65 years, and 45 were women (54%). All patients underwent posterior fusion with a mean of 11 levels fused and 33 (40%) 3-column osteotomies were performed. Among the epigenetic clocks adjusted for BMI and sex, DunedinPACE showed a significant association with ASD-FI (ß = 0.041, p = 0.002), EFS (ß = 0.696, p = 0.026), and SRS-22r (ß = 0.174, p = 0.013) scores. PC PhenoAge showed associations with ASD-FI (ß = 0.029, p = 0.028) and SRS-22r (ß = 0.159, p = 0.018) scores. PC GrimAge showed associations with ASD-FI (ß = 0.029, p = 0.037) and SRS-22r (ß = 0.161, p = 0.025) scores. Patients with postoperative complications were noted to have shorter telomere length (T/S 0.790 vs 0.858, p = 0.049), even when the analysis controlled for BMI and sex (OR = 1.71, 95% CI 1.07-2.87, p = 0.031). CONCLUSIONS: Epigenetic clocks showed significant associations with markers of frailty and disability, while patients with postoperative complications had shorter telomere length. These data suggest a potential role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers.

Association of telomere length with risk of complications in adult spinal deformity surgery: a pilot study of 43 patients.

OBJECTIVE: Risk stratification is a critical element of surgical planning. Early tools were fairly crude, while newer instruments incorporate disease-specific elements and markers of frailty. It is unknown if discrepancies between chronological and cellular age can guide surgical planning or treatment. Telomeres are DNA-protein complexes that serve an important role in protecting genomic DNA. Their shortening is a consequence of aging and environmental exposures, with well-established associations with diseases of aging and mortality. There are compelling data to suggest that telomere length can provide insight toward overall health. The authors sought to determine potential associations between telomere length and postoperative complications. METHODS: Adults undergoing elective surgery for spinal deformity were prospectively enrolled. Telomere length was measured from preoperative whole blood using quantitative polymerase chain reaction and expressed as the ratio of telomere (T) to single-copy gene (S) abundance (T/S ratio), with higher T/S ratios indicating longer telomere length. Demographic and patient data included age, BMI, and results for the following rating scales: the Adult Spinal Deformity Frailty Index (ASD-FI), Oswestry Disability Index (ODI), Scoliosis Research Society-22r (SRS-22r), American Society of Anesthesiology (ASA) classification, and Charlson Comorbidity Index (CCI). Operative and postoperative complication data (medical or surgical within 90 days) were also collected. RESULTS: Forty-three patients were enrolled, including 31 women (53%), with a mean age of 66 years and a mean BMI of 28.5. The mean number of levels fused was 11, with 21 (48.8%) combined anterior-posterior approaches. Twenty-two patients (51.2%) had a medical or surgical complication. Patients with a postoperative complication had a significantly lower T/S ratio (0.712 vs 0.813, p = 0.008), indicating shorter telomere length, despite a mild difference in age compared with patients without a postoperative complication (68 vs 63 years, p = 0.069). Patients with complications also had higher CCI scores than patients without complications (2.3 vs 3.8, p = 0.004). There were no significant differences in sex, BMI, ASD-FI score, ASA class, preoperative ODI and SRS-22r scores, number of levels fused, or use of three-column osteotomies. In a multivariate model including age, frailty, ASA class, use of an anterior-posterior approach, CCI score, and telomere length, the authors found that short telomere length was significantly associated with postoperative complications. Patients whose telomere length fell in the shortest quartile had the highest risk (OR 18.184, p = 0.030). CONCLUSIONS: Short telomere length was associated with an increased risk of postoperative complications despite only a mild difference in chronological age. Increasing comorbidity scores also trended toward significance. Larger prospective studies are needed; however, these data provide a compelling impetus to investigate the role of biological aging as a component of surgical risk stratification.

Failure in Adult Spinal Deformity Surgery: A Comprehensive Review of Current Rates, Mechanisms, and Prevention Strategies.

STUDY DESIGN: Literature review. OBJECTIVE: The aim of this review is to summarize recent literature on adult spinal deformity (ASD) treatment failure as well as prevention strategies for these failure modes. SUMMARY OF BACKGROUND DATA: There is substantial evidence that ASD surgery can provide significant clinical benefits to patients. The volume of ASD surgery is increasing, and significantly more complex procedures are being performed, especially in the aging population with multiple comorbidities. Although there is potential for significant improvements in pain and disability with ASD surgery, these procedures continue to be associated with major complications and even outright failure. METHODS: A systematic search of the PubMed database was performed for articles relevant to failure after ASD surgery. Institutional review board approval was not needed. RESULTS: Failure and the potential need for revision surgery generally fall into 1 of 4 well-defined phenotypes: clinical failure, radiographic failure, the need for reoperation, and lack of cost-effectiveness. Revision surgery rates remain relatively high, challenging the overall cost-effectiveness of these procedures. CONCLUSION: By consolidating the key evidence regarding failure, further research and innovation may be stimulated with the goal of significantly improving the safety and cost-effectiveness of ASD surgery.

Incidence of Chronic Periscapular Pain After Adult Thoracolumbar Deformity Correction and Impact on Outcomes.

OBJECTIVE: Extension of the posterior upper-most instrumented vertebra (UIV) into the upper thoracic (UT) spine allows for greater deformity correction and reduced incidence of proximal junction kyphosis (PJK) in adult spinal deformity (ASD) patients. However, it may be associated with chronic postoperative scapular pain (POSP). The goal of this study was to assess the relationship between UT UIV and persistent POSP, describe the pain, and assess its impact on patient disability. METHODS: ASD patients who underwent multilevel posterior fusion were retrospectively identified then administered a survey regarding scapular pain and the Oswestry Disability Index (ODI), by telephone. Univariate and multivariate analysis were utilized. RESULTS: A total of 74 ASD patients were included in the study: 37 patients with chronic POSP and 37 without scapular pain. The mean age was 70.5 years, and 63.9% were women. There were no significant differences in clinical characteristics, including mechanical complications (PJK, pseudarthrosis, and rod fracture) or reoperation between groups. Patients with persistent POSP were more likely to have a UT than a lower thoracic UIV (p = 0.018). UT UIV was independently associated with chronic POSP on multivariate analysis (p = 0.022). ODI score was significantly higher in patients with scapular pain (p = 0.001). Chronic POSP (p = 0.001) and prior spine surgery (p = 0.037) were independently associated with ODI on multivariate analysis. CONCLUSION: A UT UIV is independently associated with increased odds of chronic POSP, and this pain is associated with significant increases in patient disability. It is a significant clinical problem despite solid radiographic fusion and the absence of PJK.

Reduced proximal junctional failure with ligament augmentation in adult spinal deformity: a series of 242 cases with a minimum 1-year follow-up.

OBJECTIVE: Proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are well-recognized complications of long-segment spinal fusion. Previous studies have suggested that ligament augmentation can decrease rates of PJF by reducing junctional stress and strengthening upper instrumented vertebrae (UIVs) and adjacent segments. However, there is a paucity of long-term data on the efficacy of ligament augmentation in preventing PJF. In this study, the authors sought to determine the effect of ligament augmentation on rates of PJF in a cohort of adult spinal deformity patients with at least 1 year of follow-up. METHODS: They conducted a retrospective analysis of ligament augmentation in a consecutive series of surgical patients with adult spinal deformity. Data on patient demographics, surgical characteristics, and surgery for PJF were collected. The minimum follow-up was 12 months. Univariate and multivariate analyses were performed to identify factors associated with reoperation for PJF. RESULTS: The authors identified a total of 242 patients (166 women [68.6%]) with ligament augmentation whose mean age was 66 years. The mean number of fused levels was 10, with a UIV distribution as follows: 90 upper thoracic UIVs (37.2%) and 152 lower thoracic UIVs (62.8%). Compared to a historical cohort of 77 patients treated before implementation of ligament augmentation, reoperation for PJF was significantly lower with ligament augmentation (15.6% vs 3.3%, p < 0.001). In a multivariate model, only ligament augmentation (OR 0.184, 95% CI 0.071-0.478, p = 0.001) and number of fused levels (OR 0.762, 95% CI 0.620-0.937, p = 0.010) were associated with reductions in reoperation for PJF. CONCLUSIONS: Ligament augmentation was associated with significant reductions in the rate of reoperation for PJF at 12 months in a cohort of adult spinal deformity patients. The most dramatic reduction was seen among patients with lower thoracic UIV. These data suggest that in appropriately selected patients, ligament augmentation may be a valuable adjunct for PJF reduction; however, long-term follow-up is needed.