The Association of Blood Biomarkers and Body Mass Index in Knee Osteoarthritis: A Cross-Sectional Study.

OBJECTIVE: Despite massive efforts, there are no diagnostic blood biomarkers for knee osteoarthritis (KOA). This study investigated several candidate diagnostic biomarkers and the metabolic phenotype in end-stage KOA in the context of obesity. DESIGN: In this cross-sectional study, adult patients undergoing knee arthroplasty were enrolled and KOA severity was assessed using the Lequesne index. Blood biomarkers with an important role in obesity, the metabolic syndrome, or KOA (oxidized form of low-density lipoprotein [oxLDL], advanced glycation end product [AGE], soluble AGE receptor [sRAGE], fatty acid binding protein 4 [FABP4], phospholipase A2 group IIA [PLA2G2A], fibroblast growth factor 23 [FGF-23], ghrelin, leptin, and resistin) were measured using enzyme-linked immunosorbent assay (ELISA; n = 70) or Luminex technique (subgroup of n = 35). H1-NMR spectroscopy was used for the quantification of metabolite levels (subgroup of n = 31). The hip-knee-ankle angle was assessed. Multivariable and multivariate regression analysis was used to examine the relationship of biomarkers with body mass index (BMI) and KOA severity in complete case and multiple imputation analysis. RESULTS: While most of the investigated biomarkers were not associated with KOA severity, FABP4 and leptin were found to correlate with BMI and gender. Resistin was associated with Lequesne index in complete case analysis. Using a targeted metabolomics approach, BMI-dependent changes in the metabolome were hardly visible. CONCLUSIONS: Our findings confirm studies on FABP4, leptin, and resistin with regard to obesity and the metabolic syndrome. There was no association of the investigated biomarkers with KOA severity, most likely due to the patient selection (end-stage KOA patients). Based on this absence of BMI-dependent changes in the metabolome, we might assume that BMI is not correlated with KOA severity in this specific patient group.

Fatty Acid-Binding Protein 4 (FABP4) Is Associated with Cartilage Thickness in End-Stage Knee Osteoarthritis.

BACKGROUND: There is no single blood biomarker for the staging of knee osteoarthritis (KOA). The purpose of this study was to assess the relationship of obesity, serum biomarkers, the hip-knee-ankle angle (HKAA) with sonographic cartilage thickness. METHODS: We conducted a cross-sectional study of n = 33 patients undergoing knee arthroplasty. Body mass index (BMI) was recorded, and patients were grouped based on BMI. Serum blood samples were collected, and the following biomarkers were measured using the ELISA technique (subgroup of n = 23): oxidized low-density lipoprotein (oxLDL), soluble receptor for advanced glycation end-products (sRAGE), fatty acid-binding protein 4 (FABP4), membrane-bound phospholipase A2 (PLA2G2A). The HKAA was analyzed on full-length limb standing x-ray images. Cartilage thickness was assessed on ultrasound images. Multivariable regression analysis was performed to account for confounding. RESULTS: After adjusting for age, gender, and HKAA, obese patients had thicker medial femoral cartilage (ß = 0.165, P = 0.041). Furthermore, lateral cartilage thickness was negatively correlated with FABP4 level after adjusting for of age, gender, BMI, and HKAA (ß = -0.006, P = 0.001). Confirming previous studies, after adjustment, FABP4 level was associated with a higher BMI group (ß = 42.99, P < 0.001). None of the other markers (oxLDL, PLA2G2A, and sRAGE) was associated with BMI or cartilage thickness. DISCUSSION: Our results indicate that BMI has a weak, positive association with cartilage thickness in end-stage KOA patients. FABP4 levels were negatively associated with cartilage thickness. While our study is limited by a small sample size, these results further highlight the role of FABP4 as promising biomarkers of burden of disease in KOA.

The Effect of Body Mass Index and Metformin on Matrix Gene Expression in Arthritic Primary Human Chondrocytes.

OBJECTIVE: Obesity is a known risk factor for knee osteoarthritis (OA). Diabetes has been associated with progression of OA and metformin is the first-line treatment in type 2 diabetes. The effect of the body mass index (BMI) and metformin on the expression of certain matrix genes in human chondrocytes is unclear. The purpose of this study was to investigate the effect of BMI and metformin on the expression of matrix genes in primary human chondrocytes. DESIGN: Adult female patients undergoing knee arthroplasty for end-stage OA were enrolled. Primary chondrocytes were cultivated and stimulated with metformin. Matrix gene expression was analyzed using polymerase chain reaction. Clinical data were used in multivariable regression models to assess the influence of BMI and metformin stimulation on gene expression. RESULTS: A total of 14 patients were analyzed. BMI was a predictor of increased expression in ADAMTS5 (ß = -0.11, P = 0.03). Metformin slightly reduced expression in ADAMTS5 (ß = 0.34, P = 0.04), HIF-1a (ß = 0.39, P = 0.04), IL4 (ß = 0.30, P = 0.02), MMP1 (ß = 0.47, P < 0.01), and SOX9 (ß = 0.37, P = 0.03). The hip-knee-ankle angle and proton pump inhibitors (PPIs) intake were associated with reduced SOX9 expression (ß = 0.23, P < 0.01; ß = 2.39, P < 0.01). Higher C-reactive protein (CRP) levels were associated with increased MMP1 expression (ß = -0.16, P = 0.02). CONCLUSION: We found that BMI exerts a destructive effect via induction of ADAMTS5. Metformin reduced the expression of catabolic genes ADAMTS5 and MMP1 and might play a role in disease prevention. Limb malalignment and PPI intake was associated with a reduced expression of SOX9, and higher CRP levels correlated with increased MMP1 expression, indicating a destructive process.

Expectations of Lumbar Surgery Outcomes among Opioid Users Compared with Non-Users.

STUDY DESIGN: Matched cohort study. PURPOSE: To compare and describe the effect of opioid usage on the expectations of lumbar surgery outcomes among patients taking opioids and patients not taking opioids. OVERVIEW OF LITERATURE: Chronic opioid use is common among lumbar-spine surgery patients. The decision to undergo elective lumbar surgery is influenced by the expected surgery outcomes. However, the effects of opioids on patients' expectations of lumbar surgery outcomes remain to be rigorously assessed. METHODS: A total of 77 opioid users grouped according to dose and duration (54 "higher users," 30 "lower users") were matched 2:1 to 154 non-opioid users based on age, sex, marital status, chiropractic care, disability, and diagnosis. All patients completed a validated 20-item Expectations Survey measuring expected improvement with regard to symptoms, function, psychological well-being, and anticipated future spine condition. "Greater expectations" was defined as a higher survey score (possible range, 0-100) based on the number of items expected and degree of improvement expected. RESULTS: The mean Expectations Survey scores for all opioid users and all non-users were similar (73 vs. 70, p=0.18). Scores were different, however, for lower users (79) compared with matched non-users (69, p=0.01) and compared with higher users (70, p=0.01). In multivariable analysis, "reater expectations" was independently associated with having had chiropractic care (p=0.03), being more disabled (p=0.002), and being a lower-dose opioid user (p=0.03). Compared with higher users, lower users were also more likely to expect not to need pain medications 2 years after surgery (47% vs. 83%, p=0.003). CONCLUSIONS: Patient expectations of lumbar surgery are associated with diverse demographic and clinical variables. A lower dose and shorter duration of opioid use were associated with expecting more items and expecting more complete improvement compared with non-users. In addition, lower opioid users had greater overall expectations compared with higher users.

Correlation between Urine N-Terminal Telopeptide and Fourier Transform Infrared Spectroscopy Parameters: A Preliminary Study.

N-terminal telopeptide (NTX) is a bone resorption marker that is commonly referenced in clinical practice. Bone remodeling is also associated with changes in mineral components. Fourier transform infrared spectroscopy (FTIR) is utilized in the assessment of bone material properties and some parameters are reported to have associations with bone remodeling. The aim of this cross-sectional study is to investigate the relationship between uNTX levels and FTIR parameters, utilizing prospectively collected study data for patients who underwent lumbar fusion surgery. Bone specimens were taken from iliac crest (IC) and vertebrae (V). Cortical (C) and trabecular (T) bones were separately analyzed. 22 patients (mean age 60.0 years (35.9-73.3), male : female 9 : 13) were included in the final analysis. Women showed significantly higher uNTX levels (male : female, median [range] 21.0 [11.0-39.0] : 36.0 [15.0-74.0] nM·BCE/mM, p=0.033). Among women, a significant positive correlation was observed between uNTX and mineral-to-matrix ratio in IC-C. Among men, uNTX demonstrated significant negative correlation with collagen crosslinks (XLR: ratio of mature to immature collagen crosslinks) in IC-C, V-T, and V-C. In addition, uNTX was positively correlated with acid phosphate substitution (HPO4, a parameter of new bone formation) in IC-C, IC-T, and V-C. After age adjustment, HPO4 in IC-T and V-C among men showed significant positive associations with uNTX (IC-T: p=0.018, R 2 = 0.544; V-C: p=0.007, R 2 = 0.672). We found associations between FTIR parameters and uNTX in men, but not in women. The correlations between uNTX and FTIR parameters in men might suggest a better balance of bone breakdown (uNTX) and new bone formation (FTIR parameters: XLR, HPO4) than in women.

Skin Ultrasound Measurement as a Potential Marker of Bone Quality: A Prospective Pilot Study of Patients undergoing Lumbar Spinal Fusion.

Bone mineral density (BMD) is not the sole predictor of fracture development. Qualitative markers including bone collagen maturity contribute to bone fragility. Bone and related type I collagen containing connective tissues degenerate in parallel fashion. With aging, changes in skin collagen content and quality have been observed that can be detected on ultrasound (US) as a decrease in dermal thickness and an increase in reticular layer echogenicity. We hypothesized that US dermal thickness and echogenicity correlate with bone collagen maturity. Data of 43 prospectively enrolled patients (mean age 61 years, 24 females), who underwent instrumented, posterior lumbar fusion was analyzed. Besides preoperative quantitative computed tomography (QCT) and skin US measurements, intraoperative bone biopsies were obtained and analyzed with Fourier-transform infrared spectroscopy. Among men, there was no correlation between US measurements and collagen maturity. Among women, dermal layer thickness correlated negatively with collagen maturity in trabecular bone of the iliac crest (r = -0.51, p = 0.01) and vertebra (r = -0.59, p = 0.01) as well as in cortical bone of the iliac crest (r = -0.50, p = 0.02) and vertebra (r = -0.50, p = 0.04). In addition, echogenicity correlated positively with collagen maturity in trabecular vertebral bone (r = 0.59, p = 0.01). In both genders, US measurements showed no correlation with QCT BMD. In summary, ultrasound skin parameters are associated with bone quality factors such as collagen maturity, rather than bone quantity (BMD). Ultrasound of the skin may thereby be an easy and accessible take off point for diagnosis of bone collagen maturity and connective tissue degeneration in the future. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2508-2515, 2019.

Does the Addition of Either a Lateral or Posterior Interbody Device to Posterior Instrumented Lumbar Fusion Decrease Cost Over a 6-Year Period?

STUDY DESIGN: Retrospective case-control study. OBJECTIVES: Few studies have compared the costs of single-level (1) posterior instrumented fusion alone (PSF), (2) posterior interbody fusion with PSF (PLIF), and (3) lateral interbody fusion with PSF (circumferential LLIF). The purpose of this study was to compare costs associated with these procedures. METHODS: Charts were reviewed and patients followed-up with a telephone questionnaire. Medicare reimbursement data was used for cost estimation from the payer's perspective. Multivariate survival analysis was performed to assess time to elevated resource use (greater than 90% of study patients or $68 672). RESULTS: A total of 337 patients (PSF, 45; PLIF, 222; circumferential LLIF, 70) were included (63% follow-up at 6 years). PSF and circumferential LLIF patients were 3 times more likely to reach the cutoff value compared with PLIF patients (P = .017). CONCLUSIONS: Circumferential LLIF and PSF patients were more likely to have higher resource use than PLIF patients and thus incur greater costs at 6-year follow-up.

Serotonergic Antidepressants Are Associated with Increased Blood Loss and Risk for Transfusion in Single-Level Lumbar Fusion Surgery.

STUDY DESIGN: Retrospective case-control study. PURPOSE: The purpose of this study was to examine the effect of antidepressants on blood loss and transfusion requirements in spinal surgery patients. OVERVIEW OF LITERATURE: Several studies have shown an increase in perioperative bleeding in orthopedic surgery patients on antidepressant drug therapy, yet no study has examined the impact of these agents on spinal surgery patients. METHODS: Charts of patients who underwent single-level spinal fusion (posterior lumbar interbody fusion with posterior instrumentation) performed by five fellowship-trained surgeons at a tertiary spine center between 2008 and 2013, were retrospectively reviewed. Exclusion criteria included select medical comorbidities, select drug therapy, and Amercian Society of Anesthesiologists Physical Status Classification score of greater than 2. Serotonergic antidepressants were examined in multivariate analysis to assess their predictive value on estimated blood loss and risk of transfusion. RESULTS: A total of 235 patients, of which 52% were female, were included. Allogeneic blood was transfused in 7% of patients. The average estimated blood loss was 682±463 mL. Selective serotonin reuptake inhibitors were taken by 10% of all patients. Multivariable regression analysis showed that intake of selective serotonin reuptake inhibitors was a significant predictor for blood loss (average increase of 34%, p=0.015) and for the need of allogeneic blood transfusion (odds ratio, 4.550; p=0.029). CONCLUSIONS: There was a statistically significant association between selective serotonin reuptake inhibitors and both increased blood loss and risk of allogeneic red blood cell transfusion. Surgeons and perioperative providers should take these findings into account when assessing patients' preoperative risk for blood loss and transfusion.

Coronal tibiofemoral subluxation is not an independent risk factor for total knee arthroplasty in patients with moderate to severe varus-osteoarthritis: data from the "Osteoarthritis Initiative".

PURPOSE: Only few prognostic factors for progression of knee osteoarthritis are well established, including varus malalignment. The purpose of this study was to evaluate whether coronal tibiofemoral subluxation is a predictor for total knee arthroplasty. METHODS: Patients from the progression subcohort of the longitudinal database "Osteoarthritis Initiative" with moderate to severe osteoarthritis and varus malalignment of greater than 3 degrees were included. Patients who underwent total knee arthroplasty were matched with patients treated conservatively. Subluxation was measured on full limb length X-rays. Cox regression analysis was performed to retrospectively evaluate subluxation as a risk factor for total knee arthroplasty and check for a possible association between subluxation and pain at the beginning of the observation period in this study. RESULTS: A total of 215 patients were included. Cox regression demonstrated that varus malalignment increased the hazard to undergo surgery by 16% (HR 1.158, p = 0.008) while subluxation did not (HR 1.12, p = 0.11). Furthermore, subluxation was neither associated with poor WOMAC (OR 1.13, p = 0.194) nor KOOS (OR 1.11, p = 0.256) knee pain scores at the beginning of the observation period. CONCLUSION: The results presented show that subluxation is neither an independent risk factor for total knee arthroplasty, nor for poor pain scores. LEVEL OF EVIDENCE: III.