Dino Samartzis

Chronic low back pain: A heterogeneous condition with challenges for an evidence-based approach

“Chronic” low back pain (LBP), defined as present for 3 or more months, has become a major socioeconomic problem insufficiently addressed by five major entities largely working in isolation from one another – procedural based specialties, strength based rehabilitation, cognitive behavioral therapy, pain management and manipulative care. As direct and indirect costs continue to rise, many authors have systematically evaluated the body of evidence in an effort to demonstrate the effectiveness (or lack thereof) for various diagnostic and therapeutic interventions. The objective of this Spine Focus issue is not to replicate previous work in this area. Rather, our expert panel has chosen a set of potentially controversial topics for more in-depth study and discussion. A recurring theme is that chronic LBP is a heterogeneous condition, and this affects the way it is diagnosed, classified, treated, and studied. The efficacy of some treatments may be appreciated only through a better understanding of heterogeneity of treatment effects (i.e., identification of clinically relevant subgroups with differing responses to the same treatment). Current clinical guidelines and payer policies for LBP are systematically compared for consistency and quality. Novel approaches for data gathering, such as national spine registries, may offer a preferable approach to gain meaningful data and direct us towards a “results-based medicine.” This approach would require more high-quality studies, more consistent recording for various phenotypes and exploration of studies on genetic epidemiologic undertones to guide us in the emerging era of “results based medicine.”

The association of lumbar intervertebral disc degeneration on magnetic resonance imaging with body mass index in overweight and obese adults: A population‐based study

OBJECTIVE To investigate the association of being overweight or obese with the presence, extent, and severity of lumbar disc degeneration on magnetic resonance imaging (MRI) in adults. METHODS A population-based cross-sectional study of 2,599 southern Chinese volunteers was conducted. Subjects underwent radiographic and clinical assessment, and weight and height were measured. Sagittal T2-weighted MRIs of the lumbar spine were obtained. The presence, extent, and severity of disc degeneration and additional radiographic and clinical parameters were assessed. Asian-modified body mass index (BMI) (kg/m(2) ) categories were used. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS The study included 1,040 men and 1,559 women (mean age 41.9 years). Disc degeneration was noted in 1,890 subjects (72.7%). BMI was significantly higher in subjects with disc degeneration (mean 23.3 kg/m(2) ) than in subjects without degeneration (mean 21.7 kg/m(2) ) (P < 0.001). A significant increase in the number of degenerated levels (P < 0.001), global severity of disc degeneration (P < 0.001), and end-stage disc degeneration with disc space narrowing (P < 0.001) was noted with elevated BMI, in particular in overweight and obese subjects. In the adjusted multivariate logistic regression model, there was a positive linear trend (r(2) = 0.99) between BMI and the overall presence of disc degeneration in overweight (OR 1.30 [95% CI 1.03-1.62]) and obese (OR 1.79 [95% CI 1.17-2.74]) subjects. End-stage disc degeneration with disc space narrowing was significantly more pronounced in obese subjects (adjusted OR 1.72 [95% CI 1.23-2.41] [reference normal weight]). CONCLUSION Our findings, in one of the largest studies to systematically assess lumbar disc degeneration on MRI, indicated a significant association between the presence, extent, and global severity of disc degeneration with weight in overweight and obese adults.

Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3.

The role of apoptosis in the pathogenesis of intervertebral disc degeneration (IDD) remains enigmatic. Accumulating evidence has shown that the apoptotic machinery is regulated by miRNAs. We hypothesized that miRNAs might contribute to apoptosis in IDD. We have found that 29 miRNAs were differentially expressed and miR‐155 was down‐regulated in degenerative nucleus pulposus (NP). The deregulation of miR‐155 was further verified using real‐time PCR (0.56 fold, p < 0.05). Bioinformatics target prediction identified FADD and caspase‐3 as putative targets of miR‐155. Furthermore, miR‐155 inhibited FADD and caspase‐3 expression by directly targeting their 3′‐UTRs, which was abolished by mutation of the miR‐155 binding sites. In vitro up‐regulation of miR‐155 in human NP cells by transfection with lentiviral pre‐miR‐155 resulted in repression of FADD and caspase‐3; whereas knockdown of miR‐155 with lentiviral antigomiR‐155 led to over‐expression of FADD and caspase‐3. Also, Fas‐mediated apoptosis was increased when antagonizing miR‐155 and decreased when using pre‐miR‐155 in human NP cells. In addition, we presented direct evidence of NP cells undergoing apoptosis in IDD tissues using transmission electron microscopy analysis. Moreover, a combination of in situ hybridization (ISH) and immunohistochemistry (IHC) revealed that miR‐155 expressed in the cytoplasm of human NP cells with reverse correlation with FADD and caspase‐3. In summary, this is the first study addressing the underlying mechanisms of IDD in terms of apoptosis and miRNAs. Furthermore, caspase‐3 is identified as a novel target of miR‐155. Our results suggest that deregulated miR‐155 promotes Fas‐mediated apoptosis in human IDD by targeting FADD and caspase‐3, implicating an aetiological and therapeutic role of miR‐155 in IDD. Copyright

Degenerative magnetic resonance imaging changes in patients with chronic low back pain: A systematic review

Study Design. Systematic review. Objective. To systematically search for critically appraise and summarize studies that (1) evaluated the association between degenerative magnetic resonance imaging (MRI) changes and chronic low back pain (CLBP) and (2) compared surgical and nonsurgical treatment of these degenerative MRI changes. Summary of Background Data. The role of routine MRI in patients with CLBP is unclear. It is also uncertain whether or not surgical treatment of degenerative MRI changes results in alleviation of back pain. Methods. Systematic literature searches were conducted in PubMed for studies published through March 1, 2011. To evaluate whether MRI degenerative changes are associated with CLBP, studies that were designed to compare the prevalence of MRI changes among subjects with and without CLBP were sought. The prevalence odds ratio was used to compare the odds of degenerative MRI findings in subjects with CLBP to the odds of such findings among those without CLBP. To evaluate whether surgical treatment of degenerative MRI changes is associated with different outcomes compared with nonsurgical treatment, comparative studies were sought. The GRADE system as applied to describe the strength of the overall body of evidence. Results. Regarding the association of degenerative changes on MRI and CLBP, five studies were included, all of which were cross-sectional in design. On the basis of these studies, a statistically significant association was found in all but one study regarding the presence of disc degeneration and CLBP (odds ratio range: 1.8–2.8). The overall strength of evidence across studies was considered to be insufficient, however. No comparative studies of surgical versus nonsurgical treatment of degenerative MRI changes were identified. Conclusion. Although there may be an association between degenerative MRI changes and CLBP, it is unknown if these estimates accurately represent the association given the quality of included studies, lack of a direct link between degenerative MRI changes and CLBP, and heterogeneity across studies. Thus, a strong recommendation against the routine use of MRI for CLBP evaluation is made. Since there are no data evaluating the efficacy of the surgical treatment of degenerative MRI changes, a strong recommendation is made against the surgical treatment of CLBP based solely upon degenerative MRI changes. Clinical Recommendations.Recommendation 1: There is insufficient evidence to support the routine use of MRI in patients with CLBP. Recommendation: StrongRecommendation 2: Surgical treatment of CLBP based exclusively on MRI findings of degenerative changes is not recommended. Recommendation: Strong

Effectiveness of autologous chondrocyte implantation in cartilage repair of the knee: a systematic review of controlled trials.

OBJECTIVE The relative differences in effectiveness of subchondral stimulation, osteochondral grafts, and autologous chondrocyte implantation (ACI) are still unclear. It is the objective of this study to systematically review the literature on ACI compared to other treatments by clinical outcome and the quality of the repair tissue, including an assessment of the validity of these findings. METHOD The online databases PubMed, EMBASE, Cochrane Controlled Trial Register, CENTRAL, CINAHL, and BioMed were searched. Controlled trials comparing ACI with other methods of cartilage repair or placebo were included. Data on clinical outcome and the quality of the repair tissue was abstracted in duplicate. Study validity was assessed by individual components (randomization, blinded outcome assessment, sample size, attrition, percentage biopsies). RESULTS Nine studies were included. The internal validity of most of these studies was poor. Studies comparing ACI with subchondral stimulation have a higher quality and show no differences in clinical outcomes, but suggest better results in tissue quality. The high quality evidence comparing ACI with osteochondral grafts shows better clinical outcomes and higher tissue quality after ACI. CONCLUSION Among the included studies there is much inconsistency in methodological quality and findings. Regardless of these problems, the absolute differences between groups are fairly small, thus raising questions about their clinical importance. Future studies will be needed to answer the question of benefits of ACI compared to other treatments, and could profit from addressing and avoiding the problems seen in this group. Finally conclusions concerning long-term effects are still difficult.

Genetic Association Studies in Lumbar Disc Degeneration: A Systematic Review

Objective Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI) in humans. Methods A systematic literature search was conducted in MEDLINE, MEDLINE In-Process, SCOPUS, ISI Web of Science, The Genetic Association Database and The Human Genome Epidemiology Network for information published between 1990–2011 addressing genes and lumbar disc degeneration. Two investigators independently identified studies to determine inclusion, after which they performed data extraction and analysis. The level of cumulative genetic association evidence was analyzed according to The HuGENet Working Group guidelines. Results Fifty-two studies were included for review. Forty-eight studies reported at least one positive association between a genetic marker and lumbar disc degeneration. The phenotype definition of lumbar disc degeneration was highly variable between the studies and replications were inconsistent. Most of the associations presented with a weak level of evidence. The level of evidence was moderate for ASPN (D-repeat), COL11A1 (rs1676486), GDF5 (rs143383), SKT (rs16924573), THBS2 (rs9406328) and MMP9 (rs17576). Conclusions Based on this first extensive systematic review on the topic, the credibility of reported genetic associations is mostly weak. Clear definition of lumbar disc degeneration phenotypes and large population-based cohorts are needed. An international consortium is needed to standardize genetic association studies in relation to disc degeneration.

Assessment of glycosaminoglycan distribution in human lumbar intervertebral discs using chemical exchange saturation transfer at 3 T: feasibility and initial experience.

Recent studies have proposed that glycosaminoglycan chemical exchange saturation transfer (gagCEST) is associated with a loss of glycosaminoglycans (GAGs), which may be an initiating factor in intervertebral disc (IVD) degeneration. Despite its promising potential, this application has not been reported in human in vivo IVD studies because of the challenges of B0 magnetic field inhomogeneity in gagCEST. This study aimed to evaluate the feasibility of quantifying CEST values in IVDs of healthy volunteers using a clinical 3 T scanner. A single‐slice turbo spin echo sequence was used to quantify the CEST effect in various GAG phantoms and in IVDs of 12 volunteers. The phantom results indicated high correlation between gagCEST and GAG concentrations (R2 = 0.95). With optimal B0 inhomogeneity correction, in vivo CEST maps of IVDs showed robust contrast between the nucleus pulposus (NP) and the annulus fibrosus (AF) (p < 0.01), as well as higher signal in the central relative to the peripheral NP. In addition, a trend of decreasing CEST values from upper to lower disc levels was evident in NP. Our results demonstrate that in vivo gagCEST quantification in human lumbar IVDs is feasible at 3 T in combination with successful B0 inhomogeneity correction, but without significant hardware modifications. Our initial findings suggest that it would be worthwhile to perform direct correlation studies between CEST and GAGs using cadaver samples, and to extend this novel technique to studies on patients with degenerative discs to better understand its distinct imaging features relative to conventional techniques. Copyright

Disk Degeneration and Low Back Pain: Are They Fat-Related Conditions?

Low back pain (LBP) is the worlds most debilitating condition. Disk degeneration has been regarded as a strong determinant associated with LBP. Overweight and obesity are public health concerns that affect every population worldwide and whose prevalence continues to rise. Studies have indicated strong associations between overweight/obesity and disk degeneration as well as with LBP. This broad narrative review article addresses the various mechanisms that may be involved leading to disk degeneration and/or LBP in the setting of overweight/obesity. In particular, our goal is to raise awareness of the role of fat cells and their involvement via altered metabolism or the release of adipokines as well as other pathways that may lead to the development of disk degeneration and LBP. Understanding the role of fat in this process may aid in the development of novel biological therapies and technologies to halt the progression or regenerate the disk. Moreover, with genetic advancements and the appreciation of genetic epidemiology, a more personalized approach to spine care may have to consider the role of fat in any preventative, therapeutic, and/or prognosis modalities toward the disk and LBP.

Association of Abdominal Obesity with Lumbar Disc Degeneration - A Magnetic Resonance Imaging Study

Purpose To evaluate whether midsagittal (abdominal) obesity in magnetic resonance imaging (MRI), waist circumference (WC) and body fat percentage are associated with lumbar disc degeneration in early adulthood. Methods We obtained the lumbar MRI (1.5-T scanner) of 325 females and 233 males at a mean age of 21 years. Lumbar disc degeneration was evaluated using Pfirrmann classification. We analysed the associations of MRI measures of obesity (abdominal diameter (AD), sagittal diameter (SAD), ventral subcutaneous thickness (VST), and dorsal subcutaneous thickness (DST)), WC and body fat percentage with disc degeneration sum scores using ordinal logistic regression. Results A total of 155 (48%) females and 147 (63%) males had disc degeneration. AD and SAD were associated with a disc degeneration sum score of ≥3 compared to disc degeneration sum score of 0–2 (OR 1.67; 95% confidence interval (CI) 1.20–2.33 and OR 1.40; 95% CI 1.12–1.75, respectively) among males, but we found no association among females. WC was also associated with disc degeneration among males (OR 1.03 per one cm; 95% CI 1.00–1.05), but not among females. Conclusion Measures of abdominal obesity in MRI and waist circumference were associated with disc degeneration among 21-year-old males.

Pathobiology of Modic changes

PurposeLow back pain (LBP) is the most disabling condition worldwide. Although LBP relates to different spinal pathologies, vertebral bone marrow lesions visualized as Modic changes on MRI have a high specificity for discogenic LBP. This review summarizes the pathobiology of Modic changes and suggests a disease model.MethodsNon-systematic literature review.ResultsChemical and mechanical stimulation of nociceptors adjacent to damaged endplates are likely a source of pain. Modic changes are adjacent to a degenerated intervertebral disc and have three generally interconvertible types suggesting that the different Modic change types represent different stages of the same pathological process, which is characterized by inflammation, high bone turnover, and fibrosis. A disease model is suggested where disc/endplate damage and the persistence of an inflammatory stimulus (i.e., occult discitis or autoimmune response against disc material) create predisposing conditions. The risk to develop Modic changes likely depends on the inflammatory potential of the disc and the capacity of the bone marrow to respond to it. Bone marrow lesions in osteoarthritic knee joints share many characteristics with Modic changes adjacent to degenerated discs and suggest that damage-associated molecular patterns and marrow fat metabolism are important pathogenetic factors. There is no consensus on the ideal therapy. Non-surgical treatment approaches including intradiscal steroid injections, anti-TNF-α antibody, antibiotics, and bisphosphonates have some demonstrated efficacy in mostly non-replicated clinical studies in reducing Modic changes in the short term, but with unknown long-term benefits. New diagnostic tools and animal models are required to improve painful Modic change identification and classification, and to clarify the pathogenesis.ConclusionModic changes are likely to be more than just a coincidental imaging finding in LBP patients and rather represent an underlying pathology that should be a target for therapy.