Friday, August 26, 2016
The use of bone morphogenetic protein (BMP) in spine surgery remains controversial, and one of the most hotly debated topics is its association with cancer. The potential link between BMP and cancer was initially identified by Carragee et al. in 2011, and this group published another paper showing a stronger association with a high dose application of BMP-2 (AMPLIFY) in 2013.1,2 These studies were criticized for the low numbers involved and the heterogeneous cancer types reported. For example, of the 20 cancer events in the AMPLIFY group, 5 were skin cancers in a single patient and 3 more were skin cancers in another patient. Further independent analyses of the Medtronic BMP-2 data reported an increased risk of cancer, though the authors of these studies concluded that the numbers were small, the surveillance was uncertain, and the evidence supporting the link with cancer was relatively weak.3,4 With the Medtronic data having raised the possibility of an association between BMP-2 and cancer, multiple investigators performed large database analyses in order to have sufficient power to more definitively answer the question. Cooper et al. analyzed the Medicare database and found no relationship between BMP and cancer, while Lad et al. performed a similar study using the MarketScan database with the same findings.5,6 On this background, Dr. Dettori and colleagues analyzed administrative databases in Washington State that captured data on hospital discharges, cancer diagnoses, and death. They identified over 4,000 spinal fusion patients treated with BMP from 2002-2010, and matched them in a 1:3 fashion to over 12,000 non-BMP fusion patients based on age, sex, and year of treatment. The average available follow-up in the database was 4.7 years. They found an unadjusted hazard ratio of 1.07 for the risk of cancer in the BMP patients compared to the non-BMP patients, with a hazard ratio of 0.93 after adjustment for the site of surgery (i.e. cervical vs. lumbar). Neither of these were statistically significant. There were no significant differences in the rates of cancer deaths between the two groups.
This is now the third administrative database study to show no association between BMP and cancer. While the Medtronic dataset raised the possibility of a link between BMP and cancer, these further studies using large numbers of patients have called this into question. The limitations of large database studies always need to be considered when interpreting the results of these analyses. All databases are only as good as the data that is inputted, and errors in capturing BMP use and cancer likely exist. However, errors in capturing cancer diagnoses probably affect both groups equally, so this is unlikely to introduce bias. Additionally, these databases only include discharges, cancer diagnoses, and deaths within the state of Washington, so patients who migrate out of state would be lost to follow-up. The authors addressed this by performing an analysis of only patients who had renewed their license within 5 years of surgery (indicating they remained in-state residents for at least a portion of the follow-up) and found the same results. Similar to the issue of misclassification in the databases, migration would also likely affect both groups equally. While the indications for BMP use in spinal surgery and its cost-effectiveness remain debatable, the evidence indicating an association between BMP and cancer continues to weaken.
Please read Dr. Dettori's article in the August 15 issue. Does this change how you view the association between BMP and cancer? Let us know by leaving a comment on The Spine Blog.
Adam Pearson, MD, MS
Associate Web Editor
1. Carragee EJ, Chu G, Rohatgi R, et al. Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. The Journal of bone and joint surgery American volume 2013;95:1537-45.
2. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. The spine journal : official journal of the North American Spine Society 2011;11:471-91.
3. Fu R, Selph S, McDonagh M, et al. Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Annals of internal medicine 2013;158:890-902.
4. Simmonds MC, Brown JV, Heirs MK, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Annals of internal medicine 2013;158:877-89.
5. Cooper GS, Kou TD. Risk of cancer after lumbar fusion surgery with recombinant human bone morphogenic protein-2 (rh-BMP-2). Spine (Phila Pa 1976) 2013;38:1862-8.
6. Lad SP, Bagley JH, Karikari IO, et al. Cancer after spinal fusion: the role of bone morphogenetic protein. Neurosurgery 2013;73:440-9.
Friday, August 19, 2016
The treatment of chronic low back pain (CLBP) remains challenging, with most studies showing no better than modest improvements associated with surgery, intensive rehabilitation, physical therapy (PT), medications, and injections.1,2 Surgery and intensive rehabilitation have been the most rigorously studied interventions, and they seem to have similar outcomes.3 Traditional outpatient PT has not been studied in well-designed, comparative studies, yet it is recommended as first line therapy for CLBP.4 Given the lack of strong evidence supporting the use of PT to treat LBP, Dr. Eleswarapu and colleagues from Chicago used a commercial database from a large PT organization to look at patient reported outcomes before and after PT for LBP. The database included baseline and post-treatment Oswestry Disability Index (ODI) as well as the numeric pain rating scale (NPRS) at rest and with activity. Patient demographic characteristics and self-reported comorbidities were also included in the database. They identified over 4000 patients with diagnoses consistent with non-specific LBP. Their primary analysis determined the proportion of patients who improved by a predefined minimal clinically important difference (MCID) on the patient reported outcome measures (10 points on the ODI, 2 points on the NPRS). A secondary analysis evaluated patient characteristics that predicted failure to reach the MCID. Patients with a baseline ODI < 10 (21%) or NPRS < 2 at rest (32%) or with activity (9%) were excluded for the analysis of that outcome as they could not attain the MCID. Only 28.5% of patients reached the MCID for the ODI, while 59% improved more than 2 points on the NPRS at rest and 60% on the NPRS with activity. Smoking and night pain predicted failure on all outcome measures, while body mass index over 30 and receiving worker's compensation were also consistent predictors of failure.
This study is interesting as it provides insight into the effectiveness of PT for LBP in a large cohort of patients from across the United States. It has the strengths and weaknesses of all large database studies, namely that it includes a large number of patients that results in a high level of statistical power, yet is also limited by the low level of detail that the database captured. For example, important information like the duration of symptoms, use of narcotics, and presence or absence of leg pain was not recorded. The most serious limitation is probably related to the heterogeneity of the patients and treatments included. The only inclusion criterion was a diagnostic code for a diagnosis consistent with non-specific low back pain, so patients across the entire spectrum of symptom duration and severity were likely included. The fact that over 20% of patients had an ODI of less than 10 indicates that many patients had very mild symptoms. Additionally, there was no description of what "PT" actually included. Patients were likely treated with varying combinations of exercises, modalities, education, massage, and manipulation. Compliance with treatment was not recorded. As such, it is very difficult to make any conclusions about the effectiveness of PT for LBP since "PT" and "LBP" were not well-defined. This study does confirm what little we know about PT for LBP. Physical therapy seems to provide modest improvements for some LBP patients, and smoking, obesity, medical and psychiatric comorbidities, and receiving worker's compensation lead to worse outcomes. Future studies need to define what type of PT works for specific LBP diagnoses in patients with unique individual characteristics so that resources are not wasted on ineffective care. The challenge will continue to be the treatment of people with disease and patient characteristics that predict poor outcomes across all treatment modalities.
Please read Dr. Eleswarapu's article on this topic in the August 15 issue. Does this change how you view the use of PT for LBP? Let us know by leaving a comment on The Spine Blog.
Adam Pearson, MD, MS
Assocaite Web Editor
1. Chou R, Atlas SJ, Stanos SP, Rosenquist RW. Nonsurgical interventional therapies for low back pain: a review of the evidence for an American Pain Society clinical practice guideline. Spine (Phila Pa 1976) 2009;34:1078-93.
2. Mirza SK, Deyo RA. Systematic review of randomized trials comparing lumbar fusion surgery to nonoperative care for treatment of chronic back pain. Spine (Phila Pa 1976) 2007;32:816-23.
3. Brox JI, Sorensen R, Friis A, et al. Randomized clinical trial of lumbar instrumented fusion and cognitive intervention and exercises in patients with chronic low back pain and disc degeneration. Spine (Phila Pa 1976) 2003;28:1913-21.
4. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007;147:478-91.
Saturday, August 13, 2016
Much has been written about the accuracy of pedicle screw placement and the biomechanics of pedicle screw instrumentation. The literature suggests a relatively low rate of screw malposition leading to neurological deficit or reoperation. However, malpositioned screws are frequently detected intra-operatively and redirected prior to leaving the operating room. Data on the negative biomechanical effects of screw redirection are sparse, though one would assume that the strength of the screw-bone interface is compromised when the screw is redirected. In order to address this question, Dr. Goda and his colleagues from Japan performed a cadaveric biomechanical study in which they placed pedicle screws into 54 thoracolumbar vertebrae. In one third of the specimens, a screw was placed with a lateral pedicle breach and then redirected. The other two thirds had screws placed that violated the superior endplate. Half of these had the malpositioned screw redirected, and the other half had the screw left in place. Every vertebra included one redirected or malpositioned screw and one appropriately positioned screw that served as the control. Following screw placement, the pullout strength of the redirected or malpositioned screw was compared to the appropriately positioned screw in the contralateral pedicle. They found that a screw that was redirected following a lateral breach had a 24% decrease in pullout strength. Similarly, redirecting a screw following an endplate violation resulted in a 23% decrease in pullout strength. The pullout strength of a malpositioned screw that violated the endplate but was not redirected was only decreased by 8%.
The results of this study are not surprising, as malpositioning and subsequently redirecting a screw results in both violation of the cortical bone of the pedicle as well as compression of the cancellous bone. However, the clinical relevance of a 25% decrease in pullout strength is unknown, and it probably depends on the clinical situation. When pedicle screws are used to obtain fusion in a stable, degenerative condition in a patient with normal bone, such a decrease may not be clinically important. However, when being used for fixation of an unstable fracture in an osteopenic patient, a 25% loss of pullout strength could lead to hardware failure. An additional limitation of this study is that the average age of the specimens was 85, so the bone density was likely less compared to the younger population in whom pedicle screws are more frequently used. The authors also chose to study pullout strength, while failure in vivo more often involves gradual loosening due to repeated loading of the screw-bone interface. It is always difficult to extrapolate from the biomechanics lab to the clinical arena, however, this study should serve as even more motivation for surgeons to try to place screws appropriately on the first try. While the authors studied screw redirection, a more common clinical scenario is the creation of a breach with the pedicle finder that is detected prior to screw placement. It would be interesting to know what effect that has on pullout strength. Given the findings of the current study, surgeons need to consider the role of fluoroscopy and navigation and determine if these techniques increase accuracy sufficiently to justify their cost and radiation exposure.
Please read Dr. Goda's article in the August 1 issue. Does this change how you consider the effect of pedicle screw redirection? Let us know by leaving a comment on The Spine Blog.
Adam Pearson, MD, MS
Associate Web Editor
Friday, August 5, 2016
Lumbar spinal stenosis (LSS) is a difficult condition to diagnose accurately, primarily due to the lack of a reliable diagnostic test and substantial overlap with other conditions prevalent in the elderly population. Diagnostic accuracy spans a wide spectrum across different conditions, ranging from nearly perfect for displaced femur fractures to poor for fibromyalgia. Spinal stenosis likely lands in the middle of the spectrum, but diagnostic criteria are hard to define for research purposes. Diagnosing LSS involves the clinician integrating data from the history and physical exam along with imaging studies, with no single component yielding a reliable diagnosis. No diagnostic gold standard exists, and this creates a problem for researchers defining inclusion and exclusion criteria. As such, the International Society for the Study of the Lumbar Spine (ISSLS) created a task force on LSS, which was charged with creating a better set of diagnostic criteria. This group, led by Dr. Tomkins-Lane, first focused on determining the questions in the history most relevant to the diagnosis. They created a list of 14 questions germane to LSS and then went through a multiple round Delphi process using an international group of spine clinicians to determine which questions were most helpful in the diagnostic process. In the final round, 279 spine experts from 29 countries participated. The most popular questions addressed lower extremity and buttock pain with walking and relief with forward flexion. Statistical analysis revealed that the participants reached maximal diagnostic confidence after 6 questions, at about 80% certainty (based on history taking alone).
This paper won the ISSLS Prize and represents a good effort to come to a consensus about the most important components of the history related to LSS. The Delphi process has been well-validated and is likely the best way to come to an expert consensus when there is not perfect data available. The authors did not report the response rate to their internet survey, and it seems likely that majority of those contacted did not complete the study. As such, the respondents may not represent the entire international spine community, and this is suggested by the fact that 45% worked in an academic institution and the average participant had 19 years of clinical experience. That being said, most clinicians would agree that the questions selected were appropriate. This paper represents the first step in a process to create formal diagnostic criteria for LSS, which would be helpful in the research world. The authors indicate that future work will study the role of the physical exam, imaging, and electrodiagnostic studies. Integrating all of these into a diagnostic algorithm will be complex, but doing it successfully will allow for future LSS researchers to know they are comparing apples to apples. From a clinical standpoint, most spine care providers feel that diagnosing LSS involves creating a gestalt from the available history, physical exam, and imaging data. If this can be done as effectively by a diagnostic algorithm remains to be seen.
Please read Dr. Tomkins-Lane's article in the August 1 issue. Does this change how you think about diagnosing LSS? Let us know by leaving a comment on The Spine Blog.
Adam Pearson, MD, MS
Associate Web Editor
Friday, July 29, 2016
While most of the spine community has come to the conclusion that decompression leads to better results than non-operative care for symptomatic lumbar stenosis, authors from the Cochrane Collaboration seem to disagree. Dr. Zaina and colleagues published the results of their recent Cochrane review and reported that "it cannot conclude whether surgical or a conservative approach is better for lumbar spinal stenosis." A recent systematic review by Kovacs et al. included similar studies and reached a much different conclusion, namely that "decompressive surgery, with or without fusion, is more effective than continued conservative treatment".1 While both reviews included the same studies, methodological differences led to the discrepant results.2,3 A brief review of these two major studies included in the meta-analyses will help to explain the findings. The study by Malmivaara et al. was an RCT comparing laminectomy with or without fusion to non-operative care in 94 patients with symptomatic stenosis.2 This study showed a significant advantage for surgery on the Oswestry Disability Index and other outcome measures through two years of follow-up. The Spine Patient Outcomes Research Trial was the other study included in both reviews.3 This study included both a randomized and observational arm, though only the RCT was included in the reviews. By two years, 37% of the patients randomized to surgery had not undergone surgery, while 43% of those randomized to non-operative treatment had undergone surgery. This level of crossover resulted in the two randomized groups having undergone very similar treatment, which precluded any meaningful interpretation of the intention to treat analysis. While this was acknowledged in the Kovacs study that included the as-treated analysis, the current Cochrane Review authors stuck to their methodological guns and included only the intention to treat analysis in their quantitative meta-analysis (along with the Malmivaara study). As such, the meta-analysis showed no difference in surgical and non-operative outcomes.
Most of the research world has come to realize the value of well-designed observational studies for comparing treatments that are difficult to study in a randomized fashion (i.e. surgery vs. non-operative treatment), though the Cochrane Collaboration continues to include only RCTs in their analyses. While no one would question the scientific advantages of a randomized design, for medical conditions that have not been studied successfully with RCTs, one must consider the observational data available. The Maine Lumbar Spine Study and the SPORT as-treated analysis both showed significant advantages to surgery, with minimal improvement following non-operative treatment.3,4 The two Scandinavian RCTs, which were included in the Cochrane Review, also showed significant advantages for surgery.2,5 Given that all of the available randomized and observational data indicates that laminectomy results in better results than non-operative treatment (with the exception of the SPORT RCT that was compromised by crossover), it is baffling that the Cochrane Collaboration would conclude that the data is inconclusive. While a modern, level 1 study comparing surgery to non-operative treatment would be nice, it is probably not high on the priority list of funding organizations given the strength of the currently available data. The spine community generally agrees that surgery results in better outcomes than non-operative treatment for symptomatic lumbar stenosis. Future studies should focus on defining the role of the different surgical techniques.
Please read Dr. Zaina's article in the July 15 issue. Does this change how you consider the strength of the evidence supporting surgical treatment of lumbar spinal stenosis? Let us know by leaving a comment on The Spine Blog.
Adam Pearson, MD, MS
Associate Web Editor
1. Kovacs FM, Urrutia G, Alarcon JD. Surgery versus conservative treatment for symptomatic lumbar spinal stenosis: a systematic review of randomized controlled trials. Spine 2011;36:E1335-51.
2. Malmivaara A, Slatis P, Heliovaara M, et al. Surgical or nonoperative treatment for lumbar spinal stenosis? A randomized controlled trial. Spine 2007;32:1-8.
3. Weinstein JN, Tosteson TD, Lurie JD, et al. Surgical versus nonsurgical therapy for lumbar spinal stenosis. The New England journal of medicine 2008;358:794-810.
4. Atlas SJ, Keller RB, Robson D, Deyo RA, Singer DE. Surgical and nonsurgical management of lumbar spinal stenosis: four-year outcomes from the maine lumbar spine study. Spine 2000;25:556-62.
5. Amundsen T, Weber H, Nordal HJ, Magnaes B, Abdelnoor M, Lilleas F. Lumbar spinal stenosis: conservative or surgical management?: A prospective 10-year study. Spine 2000;25:1424-35; discussion 35-6.