Scott D. Boden

Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects: a prospective investigation

We performed magnetic resonance imaging on sixty-seven individuals who had never had low-back pain, sciatica, or neurogenic claudication. The scans were interpreted independently by three neuro-radiologists who had no knowledge about the presence or absence of clinical symptoms in the subjects. About one-third of the subjects were found to have a substantial abnormality. Of those who were less than sixty years old, 20 per cent had a herniated nucleus pulposus and one had spinal stenosis. In the group that was sixty years old or older, the findings were abnormal on about 57 per cent of the scans: 36 per cent of the subjects had a herniated nucleus pulposus and 21 per cent had spinal stenosis. There was degeneration or bulging of a disc at at least one lumbar level in 35 per cent of the subjects between twenty and thirty-nine years old and in all but one of the sixty to eighty-year-old subjects. In view of these findings in asymptomatic subjects, we concluded that abnormalities on magnetic resonance images must be strictly correlated with age and any clinical signs and symptoms before operative treatment is contemplated.

Surgical versus nonsurgical therapy for lumbar spinal stenosis.

BACKGROUND Surgery for spinal stenosis is widely performed, but its effectiveness as compared with nonsurgical treatment has not been shown in controlled trials. METHODS Surgical candidates with a history of at least 12 weeks of symptoms and spinal stenosis without spondylolisthesis (as confirmed on imaging) were enrolled in either a randomized cohort or an observational cohort at 13 U.S. spine clinics. Treatment was decompressive surgery or usual nonsurgical care. The primary outcomes were measures of bodily pain and physical function on the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36) and the modified Oswestry Disability Index at 6 weeks, 3 months, 6 months, and 1 and 2 years. RESULTS A total of 289 patients were enrolled in the randomized cohort, and 365 patients were enrolled in the observational cohort. At 2 years, 67% of patients who were randomly assigned to surgery had undergone surgery, whereas 43% of those who were randomly assigned to receive nonsurgical care had also undergone surgery. Despite the high level of nonadherence, the intention-to-treat analysis of the randomized cohort showed a significant treatment effect favoring surgery on the SF-36 scale for bodily pain, with a mean difference in change from baseline of 7.8 (95% confidence interval, 1.5 to 14.1); however, there was no significant difference in scores on physical function or on the Oswestry Disability Index. The as-treated analysis, which combined both cohorts and was adjusted for potential confounders, showed a significant advantage for surgery by 3 months for all primary outcomes; these changes remained significant at 2 years. CONCLUSIONS In the combined as-treated analysis, patients who underwent surgery showed significantly more improvement in all primary outcomes than did patients who were treated nonsurgically. (ClinicalTrials.gov number, NCT00000411 [ClinicalTrials.gov].).

The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report.

Study Design. A prospective randomized controlled human clinical pilot trial. Objectives. To determine the feasibility of using rhBMP-2/collagen as a substitute for autogenous bone graft inside interbody fusion cages to achieve arthrodesis in humans. Summary of Background Data. Preclinical studies have shown rhBMP-2 to be an effective substitute for autogenous bone graft, but there are no studies to date documenting such efficacy for human spine fusion. Methods. Fourteen patients with single-level lumbar degenerative disc disease refractory to nonoperative management were randomized to receive lumbar interbody arthrodesis with a tapered cylindrical threaded fusion cage filled with rhBMP-2/collagen sponge or autogenous iliac crest bone. Patients were evaluated with radiographs, sagittally reformatted computed tomography scans, and Short Form-36 and Oswestry outcome questionnaires. Results. All 11 patients who received rhBMP-2 were judged by three independent radiologists to have solid fusions (at 6, 12, and 24 months postimplantation), whereas only 2 of the 3 control patients, who received the standard treatment of autogenous iliac crest bone, were deemed to be fused. The Oswestry Disability Questionnaire scores of the rhBMP-2 group improved sooner (after 3 months) than those of the autograft group, with both groups demonstrating similar improvement at 6 months. Short Form 36 scores continued to improve up to 24 months. Conclusion. The arthrodesis was found to occur more reliably in patients treated with rhBMP-2–filled fusion cages than in controls treated with autogenous bone graft, although the sample size was limited. There were no adverse events related to the rhBMP-2 treatment. This study is one of the first to show consistent and unequivocal osteoinduction by a recombinant growth factor inhumans.

Inhibition of Osteoblast Differentiation by Tumor Necrosis Factor-α1

Tumor necrosis factor-a (TNF-a) has a key role in skeletal disease in which it promotes reduced bone formation by mature osteoblasts and increased osteoclastic resorption. Here we show that TNF inhibits differentiation of osteoblasts from precursor cells. TNF-a treatment of fetal calvaria precursor cells, which spontaneously differentiate to the osteoblast phenotype over 21 days, inhibited differentiation as shown by reduced formation of multilayered, mineralizing nodules and decreased secretion of the skeletal-specific matrix protein osteocalcin. The effect of TNF was dose dependent with an IC50 of 0.6 ng/ml, indicating a high sensitivity of these precursor cells. Addition of TNF-a from days 2‐21, 2‐14, 7‐14, and 7‐10 inhibited nodule formation but addition of TNF after day 14 had no effect. Partial inhibition of differentiation was observed with addition of TNF on only days 7‐ 8, suggesting that TNF could act during a critical period of phenotype selection. Growth of cells on collagen-coated plates did not prevent TNF inhibition of differentiation, suggesting that inhibition of collagen deposition into matrix by proliferating cells could not, alone, explain the effect of TNF. Northern analysis revealed that TNF inhibited the expression of insulin-like growth factor I (IGF-I). TNF had no effect on expression of the osteogenic bone morphogenic proteins (BMPs-2, -4, and -6), or skeletal LIM protein (LMP-1), as determined by semiquantitative RT-PCR. Addition of IGF-I or BMP-6 to fetal calvaria precursor cell cultures enhanced differentiation but could not overcome TNF inhibition, suggesting that TNF acted downstream of these proteins in the differentiation pathway. The clonal osteoblastic cell line, MC3T3-E1‐14, which acquires the osteoblast phenotype spontaneously in postconfluent culture, was also studied. TNF inhibited differentiation of MC3T3-E1‐14 cells as shown by failure of mineralized matrix formation in the presence of calcium and phosphate. TNF was not cytotoxic to either cell type as shown by continued attachment and metabolism in culture, trypan blue exclusion, and Alamar Blue cytotoxicity assay. These results demonstrate that TNF-a is a potent inhibitor of osteoblast differentiation and suggest that TNF acts distal to IGF-I, BMPs, and LMP-1 in the progression toward the osteoblast phenotype. (Endocrinology 141: 3956 ‐3964, 2000)

Experimental spinal fusion with recombinant human bone morphogenetic protein-2.

Study Design. Lumbar intertransverse process arthrodesis using recombinant human bone morphogenetic protein‐2 was performed in a previously established rabbit model for posterolateral spinal fusion and compared with fusions achieved using autogenous bone graft. Objectives. To qualitatively compare different recombinant human bone morphogenetic protein‐2 dosages and carriers and to determine the efficacy of recombinant human bone morphogenetic protein‐2 as a bone graft substitute to produce lumbar intertransverse process fusion in a validated rabbit model for posterolateral spinal fusion. Summary of Background Data. Autogenous bone was considered the most successful bone graft material used for spinal arthrodesis. Problems with its use may occur in 25‐30% of patients and prompted the search for and investigation of bone graft substitutes and osteoinductive growth factors, such as bone morphogenetic proteins. Recombinant human bone morphogenetic protein‐2 was used successfully in orthotopic sites to generate bone in animal mandibular and long bone defect models. Methods. Posterolateral intertransverse process arthrodeses were performed at L5‐L6 in 56 rabbits using recombinant human bone morphogenetic protein‐2 or autogenous bone graft. Rabbits were killed either 5 weeks later to qualitatively compare fusions achieved using different recombinant human bone morphogenetic protein‐2 dosages and carriers or 4 weeks later to compare the efficacy of recombinant human bone morphogenetic protein‐2 in achieving spinal fusion compared with using autogenous bone graft. Inspection, manual palpation, radiography, histology, and biomechanic testing were used to assess the fusion. Results. All rabbits implanted with recombinant human bone morphogenetic protein‐2 achieved solid spinal fusion by manual palpation and were fused radiographically, whereas only 42% of the autograft control fusions were solid. More mature fusions with greater trabecular bone formation were shown radiographically and histologically in rabbits implanted with the highdose recombinant human bone morphogenetic protein‐2 than with the low‐dose recombinant human bone morphogenetic protein‐2. Fusions achieved using recombinant human bone morphogenetic protein‐2 delivered in the collagen carrier were more remodeled and homogeneous compared with using recombinant human bone morphogenetic protein‐2 delivered in autograft ± collagen carrier. Fusions achieved with recombinant human bone morphogenetic protein‐2 were biomechanically stronger and stiffer than fusions achieved using autogenous bone graft. Conclusions. Recombinant human bone morphogenetic protein‐2 successfully and reliably achieved lumbar intertransverse process fusion in a validated rabbit model for posterolateral spinal fusion. Radiographically and histologically, greater and more rapid bone formation, consolidation, and remodeling were shown with recombinant human bone morphogenetic protein‐2 compared with autogenous bone graft. Fusions achieved with recombinant human bone morphogenetic protein‐2 were biomechanically stronger and stiffer than autograft fusions.Study Design Neurophysiologic reactions of cauda equina nerve roots to intermittently appliced compression were assessed for two different modes of compression using a porcine model. Objective To assess the neurephysiologic reactions of cauda equina nerve roots to intermittently applied compression. Summary of Background Data A number of experimental studies have been presented recently regarding the reaction pattern of spinal nerve roots to compression. These studies have used a continuous pressure level. For studies of pathophysiologic mechanisms behind neurogenic claudication, however, it would be more relevant to study the effects of intermittently applied compression. Methods The cauda equina was exposed and compression was applied by two inflatable balloons. Two different modes of compression were used. Fither the two balloons were inflated and deflated simultaneously (Intermittent compression), or just the caudal balloon was inflated and deflated while the cranial balloon was kept continuously inflated (continuous/intermittent compression). The experimental series were: intermittent compression at 10 mm Hg (n = 5) and 50 mm Hg (n = 5), and continuous/intermittent compression at 10 mm Hg (n = 5) and 50 mm Hg (n = 5). For both modes of compression the pressure in the balloons with intermittent inflation was maintained for 10 minutes and deflated for 5 minutes. This procedure was repeated in 8 cycles for 2 hours. Muscle action potentials were recorded in the tail muscles. Results Compression at 10 mm Hg induced similar reductions of muscle action potentials for both compression modes. At 50 mm Hg, the effects were more pronounced at continuous/intarmittent compression than at intermittent compression. The reduction of muscle action potentials was slightly more pronounced for 50 than for 10 mm Hg at intermittent compression. However, a statistically significant difference in the results was founds only between 10 and 50 mm Hg at the continuous/intermittent compression mode. Conclusions The established model allows investigation of the effects of intermittent cauda equina compression, which might be clinically more relevant than continuous compression regarding the pathophysiologic mechanisms behind neurogenic claudication.

The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects : a seven-year follow-up study.

Background: In 1989, a group of sixty-seven asymptomatic individuals with no history of back pain underwent magnetic resonance imaging of the lumbar spine. Twenty-one subjects (31%) had an identifiable abnormality of a disc or of the spinal canal. In the current study, we investigated whether the findings on the scans of the lumbar spine that had been made in 1989 predicted the development of low-back pain in these asymptomatic subjects. Methods: A questionnaire concerning the development and duration of low-back pain over a seven-year period was sent to the sixty-seven asymptomatic individuals from the 1989 study. A total of fifty subjects completed and returned the questionnaire. A repeat magnetic resonance scan was made for thirty-one of these subjects. Two neuroradiologists and one orthopaedic spine surgeon interpreted the original and repeat scans in a blinded fashion, independent of clinical information. At each disc level, any radiographic abnormality, including bulging or degeneration of the disc, was identified. Radiographic progression was defined as increasing severity of an abnormality at a specific disc level or the involvement of additional levels. Results: Of the fifty subjects who returned the questionnaire, twenty-nine (58%) had no back pain. Low-back pain developed in twenty-one subjects during the seven-year study period. The 1989 scans of these subjects demonstrated normal findings in twelve, a herniated disc in five, stenosis in three, and moderate disc degeneration in one. Eight individuals had radiating leg pain; four of them had had normal findings on the original scans, two had had spinal stenosis, one had had a disc protrusion, and one had had a disc extrusion. In general, repeat magnetic resonance imaging scans revealed a greater frequency of disc herniation, bulging, degeneration, and spinal stenosis than did the original scans. Conclusions: The findings on magnetic resonance scans were not predictive of the development or duration of low-back pain. Individuals with the longest duration of low-back pain did not have the greatest degree of anatomical abnormality on the original, 1989 scans. Clinical correlation is essential to determine the importance of abnormalities on magnetic resonance images.

An experimental lumbar intertransverse process spinal fusion model. Radiographic, histologic, and biomechanical healing characteristics.

Objective. The purpose of this investigation was to develop, characterize, and validate an animal model for lumbar intertransverse process fusion. Study Design. This study used a rabbit model to characterize the radiographic, histologic, and biomechanical properties of the intertransverse process spinal fusion healing process. Methods. Sixty adult New Zealand white rabbits underwent bilateral posterolateral spinal fusion at L5-L6 using autogenous iliac bone graft. Four of the rabbits were used as negative controls: two received bone graft without decortication of the transverse process, and two underwent decortication without bone grafting. Rabbits were killed at 2, 3, 4, 5, 6, or 10 weeks and the spinal fusions were analyzed by radiography, manual palpation, and uniaxial tensile mechanical testing or light microscopy. Results. Overall the nonunion rate was 33% in animals 4 or more weeks from surgery. Biomechanical strength and stiffness of the fusions became statistically different from the adjacent unfused control levels after the third week (P < 0.05). Tensile strength of the nonunions (1.4 times unfused control levels) was statistically less (P < 0.05) than that of the solidly fused levels (1.8 times unfused controls) in weeks 4, 5, 6, and 10. Fusion was not achieved in any of the control animals with omission of decortication or bone grafting. Light microscopic analysis showed three distinct and reproducible phases of spinal fusion healing. Conclusions. This animal model overcomes the limitations of previous models by more closely replicating the human procedure in surgical technique, graft healing environment, and outcome (i.e., a nonunion rate similar to that seen in humans). This model provides an opportunity to explore questions relevant to the biology of intertransverse process fusion and to investigate the coupling of the membranous and endochondral mechanisms of bone formation during spinal fusion.

Surgical versus nonoperative treatment for lumbar spinal stenosis four-year results of the Spine Patient Outcomes Research Trial.

Study Design. Randomized trial and concurrent observational cohort study. Objective. To compare 4 year outcomes of surgery to nonoperative care for spinal stenosis. Summary of Background Data. Surgery for spinal stenosis has been shown to be more effective compared to nonoperative treatment over 2 years, but longer-term data have not been analyzed. Methods. Surgical candidates from 13 centers in 11 US states with at least 12 weeks of symptoms and confirmatory imaging were enrolled in a randomized cohort (RC) or observational cohort (OC). Treatment was standard decompressive laminectomy or standard nonoperative care. Primary outcomes were SF-36 bodily pain (BP) and physical function scales and the modified Oswestry Disability index assessed at 6 weeks, 3 months, 6 months, and yearly up to 4 years. Results. A total of 289 patients enrolled in the RC and 365 patients enrolled in the OC. An as-treated analysis combining the RC and OC and adjusting for potential confounders found that the clinically significant advantages for surgery previously reported were maintained through 4 years, with treatment effects (defined as mean change in surgery group minus mean change in nonoperative group) for bodily pain 12.6 (95% confidence interval [CI], 8.5–16.7); physical function 8.6 (95% CI, 4.6–12.6); and Oswestry Disability index −9.4 (95% CI, −12.6 to −6.2). Early advantages for surgical treatment for secondary measures such as bothersomeness, satisfaction with symptoms, and self-rated progress were also maintained. Conclusion. Patients with symptomatic spinal stenosis treated surgically compared to those treated nonoperatively maintain substantially greater improvement in pain and function through 4 years.

Laparoscopic anterior spinal arthrodesis with rhBMP-2 in a titanium interbody threaded cage.

Anterior lumbar interbody arthrodesis is commonly performed for conditions involving infection, deformity, and instability. The purpose of this investigation was to determine the effective dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone graft substitute inside a titanium threaded interbody fusion cage using a nonhuman primate model of laparoscopic anterior lumbar interbody arthrodesis. Eight adult rhesus monkeys underwent laparoscopic exposure of the lumbosacral spine followed by insertion of a hollow titanium threaded cylindrical cage (Sofamor-Danek, Memphis, TN, U.S.A.). Before insertion, the chamber of the cage was filled with a collagen sponge delivery vehicle soaked with either 0 mg/ml (sham, buffer only), 0.75 mg/ml (low dose), or 1.5 mg/ml (high dose) of rhBMP-2 (Genetics Institute, Cambridge, MA, U.S.A.). Fusions were evaluated in a blinded fashion with plain radiographs and computed tomography (CT) scans 12 and 24 weeks after surgery, and by manual palpation and histology after euthanasia 24 weeks after surgery. All five monkeys treated with a cage filled with rhBMP-2 obtained a solid fusion as assessed by manual palpation. The two monkeys that received no growth factor did not achieve solid fusions. Plain radiographs were of limited value, with fusions best assessed on sagittally reconstructed CT scans. Scans from the two animals treated without growth factor showed ingrowth of bone only into the outer edges of the cage, but not through the center. Scans from the rhBMP-2-treated animals demonstrated arthrodesis with continuous bone growth through the cage. Histologic analysis demonstrated normal mature trabecular bone surrounding and growing through the cages, which correlated with the CT scan findings. We conclude that rhBMP-2 delivered in a threaded titanium interbody cage can serve as a bone graft substitute in a nonhuman primate model. Sagittal reconstructed CT may be a better method to assess for fusion with this device.

Posterolateral intertransverse process spinal arthrodesis with rhBMP-2 in a nonhuman primate: important lessons learned regarding dose, carrier, and safety.

Recombinant osteoinductive proteins have been used successfully in canine and rabbit models of posterolateral intertransverse process arthrodesis, but little is known about the ability of these compounds to achieve fusion in nonhuman primates. The goals of this investigation were to compare different combinations of recombinant human bone morphogenetic protein-2 (rhBMP-2) dosages and carriers in a nonhuman primate model of posterolateral intertransverse process spinal fusion and to determine the feasibility of using rhBMP-2 in the presence of exposed dura in a laminectomy model. Posterolateral intertransverse process arthrodeses were performed at L4-5 in 29 rhesus monkeys. The most striking findings were as follows: rhBMP-2 could induce bone in a nonhuman primate spine; the presence of a laminectomy defect with exposed dura did not preclude the safe use of rhBMP-2 for posterolateral fusion; soft tissue compression of the collagen sponge carrier prevented bone induction at standard BMP doses, presumably due to squeezing of the protein out of the sponge; and longer rhBMP-2 loading time into the collagen carrier and mechanical protection from the soft tissue compression both allowed more bone induction at a lower dose of rhBMP-2.