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Background: C5 nerve palsy is a known complication of cervical spine surgery. The development and etiology of this complication are not completely understood. The purpose of the present study was to determine whether rotation of the cervical spinal cord predicts the development of a C5 palsy.Methods: We performed a retrospective review of prospectively collected spine registry data as well as magnetic resonance images. We reviewed the records for 176 patients with degenerative disorders of the cervical spine who underwent anterior cervical decompression or corpectomy within the C4 to C6 levels. Our measurements included area for the spinal cord, space available for the cord, and rotation of the cord with respect to the vertebral body.Results: There was a 6.8% prevalence of postoperative C5 nerve palsy as defined by deltoid motor strength of ≤ 3 of 5. The average rotation of the spinal cord (and standard deviation) was 2.8° ± 3.0°. A significant association was detected between the degree of rotation (0° to 5° versus 6° to 10° versus ≥ 11°) and palsy (point-biserial correlation = 0.94; p < 0.001). A diagnostic criterion of 6° of rotation could identify patients who had a C5 palsy (sensitivity = 1.00 [95% confidence interval, 0.70 to 1.00], specificity = 0.97 [95% confidence interval, 0.93 to 0.99], positive predictive value = 0.71 [95% confidence interval, 0.44 to 0.89], negative predictive value = 1.00 [95% confidence interval, 0.97 to 1.00]).Conclusions: Our evidence suggests that spinal cord rotation is a strong and significant predictor of C5 palsy postoperatively. Patients can be classified into three types, with Type 1 representing mild rotation (0° to 5°), Type 2 representing moderate rotation (6° to 10°), and Type 3 representing severe rotation (≥ 11°). The rate of C5 palsy was zero of 159 in the Type-1 group, eight of thirteen in the Type-2 group, and four of four in the Type-3 group. This information may be valuable for surgeons and patients considering anterior surgery in the C4 to C6 levels. [ABSTRACT FROM AUTHOR]

Study Design/setting: Retrospective review of a consecutive, nonrandomized series operated on by 2 surgeons. Objective: To evaluate the clinical and radiographic effectiveness of a silicated hydroxyapatite ceramic as a bone graft substitute in a series of patients undergoing posterolateral instrumented lumbar fusion. Summary Of Background Data: Newer-generation synthetic ceramics have been refined to maximize their host-graft interaction and stimulation of new tissue formation, including silicate-substitution. Methods: An independent radiologist interpreted the computed tomography images at 6, 12, and 24 months after surgery. Forty-two patients with 1- or 2-level lumbar degenerative disorders underwent posterior laminectomy (when indicated) and posterolateral fusion with instrumentation. Surgical levels included 15 patients who underwent 2-level and 27 single-level fusion procedures (57 levels operated on in total). Results: The average back pain scores improved from 5.6 ± 2.5 preoperative to 2.1 ± 2.5 at follow-up (P < 0.05). Similar results were seen with leg pain improvement from 5.8 ± 2.5 to 1.4 ± 1.9 (P < 0.05). At 6 months, 35% of levels revealed fusion, which increased to 76.2% and 76.5% at 12 and 24 months, respectively. No evidence of ectopic bone formation or osteolysis was noted. Conclusion: In this study, a silicated calcium phosphate-based ceramic has been shown to be effective as a graft substitute and eliminate the need for autogenous iliac crest bone graft. The results confirm radiographic healing in posterolateral instrumented lumbar fusion at 24-months follow-up. The clinical outcomes also substantiate significant pain improvement consistent with published data in the literature compared with other bone graft alternatives. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this paper was to compare the reoperation rates, timing and causes between decompression alone and decompression plus fusion surgeries for degenerative lumbar diseases through a systematic review of the published data., Methods: A search of the literature was conducted on PubMed/MEDLINE, EMBASE and the Cochrane Collaboration Library. Reports that included reoperations after decompression alone and/or decompression plus fusion surgeries were selected using designed eligibility criteria. Comparative analysis of reoperation rates, timing and causes between the two surgeries was conducted., Results: Thirty-two retrospective and three prospective studies were selected from 6401 papers of the literature search. The analysis of data reported in these studies revealed that both surgeries resulted in similar reoperation rates after the primary surgery. However, majority of reoperations following the fusion surgeries were due to adjacent-segment diseases, and following the decompression alone surgeries were due to the same-segment diseases. Reoperation rates were not found to decrease in patients operated more recently than those operated in early times., Conclusions: Reoperation rates were similar following decompression alone or plus fusion surgeries for degenerative lumbar diseases. However, different underlying major causes exist between the two surgeries. There is no evidence showing that the reoperation rate has a trend to decline with newer surgical techniques used. The exact mechanisms of reoperation after both surgeries are still unclear. Further researches are necessary to investigate the mechanisms of reoperation for improvement of surgical techniques that aim to delay or prevent reoperation after lumbar surgery. These slides can be retrieved under Electronic Supplementary Material.

Purpose: Lumbar disc surgery is a common procedure in the USA. It is frequently performed with good or excellent results in most patients. This article reviews common causes of persistent radiculopathy after surgical intervention., Methods: We performed an extensive review of the literature as well as applying our own experience., Results: Common causes of persistent leg pain following operative intervention include re-herniation, epidural fibrosis, biochemical/physiologic changes in the nerve root, and psychosocial issues., Conclusions: Patients with persistent leg pain after surgical treatment of lumbar disc herniation can pose a challenging clinical problem. Summary of these topics and available treatment options are reviewed.

Central cord syndrome (CCS) represents a clinical phenomenon characterized by disproportionately greater motor impairment of the upper than of the lower extremities, bladder dysfunction. CSS is the most common form of incomplete traumatic spinal cord injury. The initial description of CSS was reported in 1887 secondary to cervical spinal trauma. However, recent literature describes a heterogenous injury patterns including high-energy and low-energy mechanisms and bimodal patient age distributions. Pathophysiology of clinical symptoms and neurological deficits often is affected by preexisting cervical spondylosis. Urgent clinical diagnosis is dependent on neurological examination and imaging studies. Treatment of CSS is dependent on injury mechanism and compressive lesions, neurological examination, preexisting cervical pathology, and patient-specific comorbidities. This article will review the current concepts in diagnosis, pathophysiology, and treatment of CSS with a highlighted case example.

Study Design: Cross-sectional study reviewing 62 magnetic resonance imaging or computed tomography scans from consecutive adult patients with scoliotic spinal deformity in the thoracolumbar spine., Objective: To investigate the variation in anatomic position of retroperitoneal vessels in relationship to curve direction, location, magnitude, and axial rotation of curves in adult scoliosis., Summary of Background Data: The minimally invasive lateral approach to the thoracolumbar spine avoids manipulation of abdominal and retroperitoneal structures and decreases risk of injury to paraspinal musculature. In adult patients with scoliosis, the varying anatomic relationship between retroperitoneal vessels and intervertebral disk spaces can increase the risk of vascular injury., Materials and Methods: Axial images were used to measure the anterior-posterior diameter of the inferior vertebral endplate with respect to the disk space perpendicular to the widest length of the disk. The overlap of the retroperitoneal vessels with the endplate were measured at the cephalad end vertebra, apex, and caudad end vertebra of each curve. Overlap and accessible disk space for individual disk spaces were also measured., Results: There was a significant difference in percentage overlap of the apex and cephalad vertebral endplate and inferior vena cava in right versus left-sided curves (P=0.002). Overlap between the inferior vertebral endplate and inferior vena cava at the cephalad, apex, and caudad end of the curve was significantly different between thoracolumbar and lumbar curves (P<0.05). Axial rotation significantly affected vessel overlap at multiple curve locations. There was a statistically significant difference in accessible disk space when approaching the curve from the concavity versus convexity., Conclusions: Overlap between retroperitoneal vessels and inferior vertebral endplates at the disk level in scoliotic spines varies significantly with direction of the curvature, level of the deformity, and degree of axial rotation. There is decreased accessible disk space and increased vessel overlap on the concavity of the curve. Surgeons, as usual, will take an individualized case by case approach to avoid approach-related vascular complications, but the general relationships reported in this study can guide side of approach.

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Study Design: Retrospective study., Objective: To assess the relation between exposure to epidural steroid injection (ESI) before surgery and occurrence of surgical site infection (SSI) for degenerative lumbar spine conditions., Summary of Background Data: The effect of local ESI on the occurrence of SSI is controversial., Methods: Patients who underwent surgery for degenerative lumbar spine conditions at two centers between 2005 and 2015 were identified. Primary outcome measure was SSI within 90 days requiring surgical intervention., Results: A total of 5311 patients (age 57 ± 16 years) were analyzed of which 945 (18%) had at least one ESI within 90 days of surgery. One hundred thirty-four (2.5%) patients developed an SSI requiring reoperation. No association of exposure or dose-response relationship was identified between ESI and SSI for any of the time periods (90-, 30-, and 30-90-day). Five (1.7%) of the 290 patients who had at least one ESI within 30 days before surgery had a postoperative infection compared to 129 (2.6%) of the 5021 in the non-ESI group (unadjusted odds ratio: 0.67, 95% CI: 0.27-1.64, P = 0.376). Fifteen (2.0%) of the 761 patients who had at least one ESI within 30 to 90 days before surgery had a postoperative infection, compared to 119 (2.6%) of the 4550 in the non-ESI group (unadjusted odds ratio: 0.75, 95% CI: 0.44-1.29, P = 0.296)., Conclusion: In this retrospective study we investigated whether an ESI and its timing influences the postoperative risk of an SSI. We found no association-exposure or dose-response relationship-between ESI and postoperative infection, even after adjusting for potential confounders, for any of the time periods (90-, 30-, and 30-90-day ESI). In addition, we did find that longer hospital stay, greater EBL, posterior approach, and drain placement were associated with higher infection rates.Level of Evidence: 3., (Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.)

Lumbar spine surgery is often associated with complications in the perioperative and postoperative periods. Evidence-based literature in the prevention and management of adverse events, including surgical site infection, venous thromboembolism, and positioning-related complications, has advanced the understanding of the etiology of these complications and preventive measures. Cost-effective measures to reduce intraoperative bleeding can lead to a lower incidence of infection, disease transmission, and morbidity in the postoperative period. As the healthcare system receives additional scrutiny with value-based assessments, surgeons, hospitals, and administrators will need to make critical decisions to prevent and manage the complications of lumbar spine surgery.

Background Context: Surgical treatment for lumbar degenerative disc disease (DDD) has been associated with highly variable results in terms of postoperative pain relief and functional improvement. Many experts believe that DDD should be considered a chronic pain disorder as opposed to a degenerative disease. Genetic variation of the catechol-O-methyltransferase (COMT) gene has been associated with variation in human pain sensitivity and response to analgesics in previous studies., Purpose: To determine whether genetic variation of COMT is associated with clinical outcome after surgical treatment for DDD., Study Design: Prospective genetic association study., Patient Sample: Sixty-nine patients undergoing surgical treatment for lumbar DDD. Diagnosis was based on documentation of chronic disabling low back pain (LBP) present for a minimum of 6 months and unresponsive to supervised nonoperative treatment, including activity modification, medication, physical therapy, and/or injection therapy. Plain radiographs and magnetic resonance imaging revealed intervertebral disc desiccation, tears, and/or collapse without focal herniation, nerve root compression, stenosis, spondylolisthesis, spondylolysis, or alternative diagnoses., Outcome Measures: Oswestry Disability Index (ODI) and visual analog score (VAS) for LBP., Methods: Surgical treatment included 65 instrumented fusions and four disc arthroplasty procedures. All patients completed preoperative and 1-year postoperative ODI questionnaires. DNA was extracted from a sample of venous blood, and genotype analysis was performed for five common COMT single nucleotide polymorphisms (SNPs). Potential genetic association between these COMT SNPs and the primary outcome variable, 1-year change in ODI, was investigated using both single-marker and haplotype association analyses. Association with VAS scores for LBP was analyzed as a secondary outcome variable., Results: Single-marker analysis revealed that the COMT SNP rs4633 was significantly associated with greater improvement in ODI score 1 year after surgery (p=.03), with individuals homozygous for the less common "T" allele demonstrating the largest improvement in ODI. Haplotype analysis of four COMT SNPs, rs6269, rs4633, rs4818, and rs4680, also identified a common haplotype "ATCA" (haplotype frequency of 39.3% in the study population) associated with greater improvement in ODI (p=.046). The greatest mean improvement in ODI was observed in patients homozygous for the "ATCA"COMT haplotype. A nonsignificant trend was observed between SNP rs4633 and greater improvement in VAS score for LBP., Conclusions: This is the first study to report an association between surgical treatment success in DDD patients and genetic variation in the putative pain sensitivity gene COMT. These findings require replication in other DDD populations but suggest that genetic testing for pain-relevant genetic markers such as COMT may provide useful clinical information in terms of predicting outcome after surgery for patients diagnosed with DDD., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Study Design: Prospective observational study., Objective: To determine whether polymorphic variations of the guanosine triphosphate (GTP) cyclohydrolase 1 gene (GCH1) are associated with different outcomes in patients undergoing surgical treatment for lumbar degenerative disc disease (DDD)., Summary of Background Data: GCH1, the gene encoding the rate-limiting enzyme in tetrahydrobiopterin synthesis, has been strongly implicated as a determinant of pain experience in previous animal and human studies. METHODS.: A total of 69 patients undergoing surgical treatment for lumbar DDD were prospectively enrolled. Genomic DNA was extracted from a venous blood sample, and DNA sequence analysis was performed of GCH1. Surgery included 65 instrumented fusions and 4 disc arthroplasty procedures. Patients were observed prospectively for 1 year following surgery. Allelic and genotype frequencies were calculated for each of 14 single nucleotide polymorphisms (SNPs). One-year postoperative Oswestry Disability Index (ODI) scores were compared to preoperative scores and the absolute change in ODI score was used to perform genetic association analyses on the basis of both individual SNP markers as well as commonly observed haplotypes for the entire gene sequence., Results: Single marker analysis revealed 1 SNP (rs998259; minor allele T) that was significantly associated with improvement in both absolute ODI score (P = 0.030) and Numerical Rating Scale back pain scores (P = 0.033) following surgery. Haplotype analysis identified a common GCH1 haplotype ("CACTTGTTTGAC") with a sample frequency of 12.3%, which was highly associated with improvement in absolute ODI score (P = 0.04). This haplotype frequency reflects the existence of both heterozygous and homozygous individuals in the study population. The presence of 1 unit of this haplotype was associated with an improvement in postoperative ODI score of 15.34 relative to the absence of this haplotype (P = 0.04)., Conclusion: Preliminary results from this pilot genetic study of patients undergoing surgery for DDD suggests that the T allele at rs998259 of GCH1 may be associated with improved outcomes 1 year following surgery.

Background Context: Morbidity associated with autologous bone graft harvest is an important factor in determining the utility of expensive alternatives such as recombinant bone morphogenic protein. The most frequently reported complication associated with graft harvest is chronic pain., Purpose: To prospectively determine the degree of pain and morbidity associated with autologous iliac crest bone graft harvest and its effect on activities of daily living., Study Design: Prospective observational cohort study., Patient Sample: One hundred ten adult patients undergoing elective posterior lumbar spinal fusion surgery involving autologous iliac crest bone graft harvest., Outcome Measures: Patient self-reported Visual Analog Scale (VAS) scores for pain and a study-specific questionnaire regarding activities of daily living., Methods: One hundred ten patients were prospectively enrolled. Postoperative VAS scores (0-100) for harvest site pain were obtained at 6-week, 6- and 12-month follow-up. Patients completed a 12-month questionnaire regarding the persistence of specific symptoms and resulting limitation of specific activities., Results: One hundred four patients were available for 1-year follow-up. Mean VAS pain scores (scale 0-100) at 6 weeks, 6 and 12 months were 22.7 (standard deviation [SD], 25.9), 15.9 (SD, 21.5), and 16.1 (SD, 24.6), respectively. At 12 months, 16.5% reported more severe pain from the harvest site than the primary surgical site, 29.1% reported numbness, and 11.3% found the degree of numbness bothersome, whereas 3.9% were bothered by scar appearance. With respect to activity limitations resulting from harvest site pain at 1 year, 15.1% reported some difficulty walking, 5.2% with employment, 12.9% with recreation, 14.1% with household chores, 7.6% with sexual activity, and 5.9% irritation from clothing., Conclusions: There is a significant rate of persistent pain and morbidity from iliac crest bone graft harvest when associated with elective spine surgery. Mean pain scores progressively decline over the first postoperative year. Nevertheless, harvest site pain remains functionally limiting in a significant percentage of patients 1 year after surgery. Rates of functional limitation are higher than previously reported and may be because of increased sensitivity of the prospective study design and targeted investigation of these specific symptoms. Validity of these findings is necessarily limited by patient ability to discriminate harvest site pain from alternative sources of back and buttock pain.

Background Context: The CHARITE artificial disc, a lumbar spinal arthroplasty device, was approved by the United States Food and Drug Administration in 2004 based on two-year safety and effectiveness data from a multicenter, prospective, randomized investigational device exemption (IDE) study. No long-term, randomized, prospective study on the CHARITE disc or any other artificial disc has been published to date., Purpose: The purpose of this study was to compare the safety and effectiveness at the five-year follow-up time point of lumbar total disc replacement using the CHARITE artificial disc (DePuy Spine, Raynham, MA) with that of anterior lumbar interbody fusion (ALIF) with BAK cages and iliac crest autograft, for the treatment of single-level degenerative disc disease from L4 to S1, unresponsive to nonoperative treatment., Study Design/setting: Randomized controlled trial-five-year follow-up., Patient Sample: Ninety CHARITE patients and 43 BAK patients., Outcome Measures: Self-reported measures: visual analog scale (VAS); validated Oswestry disability index (ODI version 1.0); Short-Form 36 Questionnaire, and patient satisfaction. Physiologic measures: radiographic range of motion, disc height, and segmental translation. Functional measures: work status., Methods: Of the 375 subjects enrolled in the CHARITE IDE trial, 277 were eligible for the five-year study and 160 patients thereof completed the five-year follow-up. The completers included 133 randomized patients. Overall success was defined as improvement> or =15 pts in ODI vs. baseline, no device failure, absence of major complications, and maintenance or improvement of neurological status. Additional clinical outcomes included an ODI questionnaire as well as VAS, SF-36, and patient satisfaction surveys. Work status was tracked for all patients. Safety assessments included occurrence and severity of adverse events and device failures. Radiographic analyses such as index- and adjacent-level range of motion, segmental translation, disc height, and longitudinal ossification were also carried out., Results: Overall success was 57.8% in the CHARITE group vs. 51.2% in the BAK group (Blackwelder's test: p=0.0359, Delta=0.10). In addition, mean changes from baseline for ODI (CHARITE: -24.0 pts vs. BAK: -27.5 pts), VAS pain scores (CHARITE: -38.7 vs. BAK: -40.0), and SF-36 questionnaires (SF-36 Physical Component Scores [PCS]: CHARITE: 12.6 pts vs. BAK: 12.3 pts) were similar across groups. In patient satisfaction surveys, 78% of CHARITE patients were satisfied vs. 72% of BAK patients. A total of 65.6% patients in the CHARITE group vs. 46.5% patients in the BAK group were employed full-time. This difference was statistically significant (p=0.0403). Long-term disability was recorded for 8.0% of CHARITE patients and 20.9% of BAK patients, a difference that was also statistically significant (p=0.0441). Additional index-level surgery was performed in 7.7% of CHARITE patients and 16.3% of BAK patients. Radiographic findings included operative and adjacent-level range of motion (ROM), intervertebral disc height and segmental translation. At the five-year follow-up, the mean ROM at the index level was 6.0 degrees for CHARITE patients and 1.0 degrees for BAK patients. Changes in disc height were also similar for both CHARITE and BAK patients (0.7 mm for both groups, p=0.9827). Segmental translation was 0.4 and 0.8mm in patients implanted with CHARITE at L4-L5 vs. L5-S1, respectively, and 0.1mm in BAK patients., Conclusions: The results of this five-year, prospective, randomized multicenter study are consistent with the two-year reports of noninferiority of CHARITE artificial disc vs. ALIF with BAK and iliac crest autograft. No statistical differences were found in clinical outcomes between groups. In addition, CHARITE patients reached a statistically greater rate of part- and full-time employment and a statistically lower rate of long-term disability, compared with BAK patients. Radiographically, the ROMs at index- and adjacent levels were not statistically different from those observed at two-years postsurgery.

Background Context: Anterior cervical plates are commonly used to provide immediate stabilization after a variety of cervical spine procedures. It has been assumed that the ideal position for anterior cervical spine plates is centered in the horizontal plane without significant angulation and without overlap of adjacent unfused levels. Nevertheless, postoperative radiographs often demonstrate actual plate position to be lateralized, rotated, or encroaching on the adjacent disc space. There have been no reported systematic studies examining the effect of variations in plate position in a large clinical population., Purpose: To evaluate the association between plate position and short-term clinical outcomes after anterior cervical discectomy and instrumented fusion (ACDF)., Study Design/setting: Review of prospectively collected clinical outcomes measures and radiographs., Patient Sample: Patients undergoing ACDF surgery by a group of spine surgical specialists at a single institution., Outcome Measures: Direct and calculated plain radiographic measurements, visual analog scores for neck and arm pain, and SF-36 scores., Methods: The study population included 200 patients undergoing a one-, two-, or three-level ACDF with instrumentation. Thirteen separate direct measurements and two calculated values of plate position on immediate postoperative radiographs, including lateralization, rotation, and proximity to adjacent disc spaces, were performed in blinded fashion by 3 independent reviewers. Statistical correlation with prospectively collected patient outcomes measures, including VAS for neck and arm pain and SF-36 scores, was performed., Results: In the study population, average plate position was 3.3 mm from the cephalad disc space, 6.4 mm from the caudal disc space, 3.9 degrees angulation in the frontal plate, and 26% laterally displaced from the midline. At average 18.6 months of follow-up, no significant association was identified between any plate position measure and clinical outcomes., Conclusions: The use of anterior cervical plating by experienced spine surgeons is associated with variation in terms of plate position on postoperative radiographs. Within the range of positions analyzed in this study, no significant association was found between lateralized or rotated plates or plates placed in proximity to adjacent disc spaces and worse short-term clinical outcomes. It should be emphasized that these results and conclusions are based on relatively short-term clinical follow-up and that the long-term effects of variation in implant position remain unknown.

This study addressed radiographically the evaluation, presence, location, and degree of subsidence with secondary focus on the various clinical parameters and outcomes in 32 patients who underwent anterior cervical discectomy and fusion (ACDF) with tricortical iliac crest bone grafts and rigid anterior plate fixation. Postoperative follow-up plain radiographs were evaluated to determine subsidence on lateral neutral images by measuring the change in height of interscrew distance (ISD) and anterior (AVD), mid (MVD), and posterior (PVD) vertebral endplate-to-endplate vertical distances. Clinical functional outcome and various risk factors were also addressed. A 100% fusion rate was achieved, no instrumentation-related complications were noted, and mild graft subsidence occurred in each patient after the initial 2 months of surgery. Mean AVD, MVD, and PVD were 1.2 mm, 0.4 mm and 0.6 mm, respectively. Mean ISD was 0.6 mm. Percent change for AVD, MVD, PVD, and ISD was 2.3%, 0.8%, 1.2%, and 1.2%, respectively. Subsidence was more pronounced at the anterior vertebral graft-endplate interface (P < .05). Satisfactory clinical results were reported in 90.9% of the patients. With such a sample size, age, sex, smoking status, plate design, graft type, and operative or number of fused levels did not demonstrate statistically significant differences to the degree of subsidence. This paper has shown that ACDF with tricortical bone grafts and rigid plating is associated with slight subsidence, graft load-sharing, high fusion rate, and excellent clinical outcome.

Background Context: Conditions requiring posterior lumbar spinal fusion remain a clinical challenge. Achieving arthrodesis using autogenous bone graft is inconsistent when rigid internal fixation such as transpedicular instrumentation is applied. Synthetic materials, particularly calcium phosphate-based ceramics, have shown promise for spine fusion applications, especially when combined with autograft. Silicate substitution has been shown to enhance the bioactivity of calcium phosphates and may obviate the need for autologous supplementation., Purpose: Determine efficacy of silicated calcium phosphate (Si-CaP) compared with autograft to generate solid lumbar fusion., Study Design: Comparison of healing of instrumented posterolateral lumbar fusion in ewes at 2 and 6 months using Si-CaP or iliac crest autograft., Methods: Eighteen skeletally mature ewes underwent implantation of either autograft or Si-CaP in the space spanning the L4-L5 transverse process. In vivo quantitative computed tomography (CT) scans were made at 2-month intervals and after euthanasia. Harvested spine segments were radiographed and biomechanically tested in bending at 6 months. Histological assessments were made at 2 and 6 months., Results: Animals receiving Si-CaP graft were biomechanically and radiographically equivalent to those receiving autograft. Fusion mass density and volume were higher for the Si-CaP group throughout the healing period. Si-CaP regenerated normal bone tissue morphology, cellularity, and maturation with no inflammatory responses despite the fact that no autograft, bone marrow aspirate, or blood was mixed with the material. Histomorphometrically, fusion mass was higher for Si-CaP and bony bridging was equivalent when compared with autograft treatment., Conclusions: Si-CaP was biomechanically, radiographically, and histologically equivalent to autograft in generating a solid, bony, intertransverse process fusion in an ovine model. Both treatment groups achieved 100% bridging fusion after 6 months of healing.

Study Design: Retrospective study., Objectives: To determine the frequency of pedicle screw violation of superior nonfused facet joints adjacent to the most cephalad pedicle screws after a midline approach for lumbar fusion., Summary of Background Data: Facet-joint violations have been evaluated in patients undergoing lumbar pedicle screw instrumentation and fusion with a Wiltse muscle-splitting approach, but not via the more common midline approach., Methods: Between 1995 and 2003, 204 patients underwent this procedure. Computed tomography scans (within 1 year postsurgery) were evaluated independently for superior facet-joint violation. chi tests were used to examine bivariate associations of superior level facet-joint violation, patient age, construct level, diagnosis, and revision status for significance (P < or = 0.05)., Results: Superior-level facet-joint violation occurred in 24% of patients and 15% of screws, twice as often on the left side (P = 0.0396) than on the right, more frequently in single than in multiple-level procedures (P < 0.0001), and most frequently with the most cephalad screws at L5 (48%). We found no significant associations between violation rates and other designated parameters., Conclusion: The left side, single-level fusion, and most cephalad pedicle screws at L5 are targets for interventions to reduce pedicle violations in this procedure.

The current debate over the efficacy of lumbar fusion for low back pain has not been settled. Fritzell et al published a landmark paper entitled "Lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish lumbar spine study group." Their goal was to provide objective evidence supporting lumbar fusion. While it was well designed and important to our knowledge base, it has limitations. We set out to review their work in an unbiased yet critical manner. Our goals are to summarize the strengths and weaknesses of the paper, place it in the context of current knowledge, and highlight its significance for present-day practice and research. From technical and study design perspectives, Fritzell et al were able to validate the use of lumbar fusion for the treatment of low back pain. However, their use of "usual nonoperative" care and nonspecific definition of low back pain precluded a truly genuine comparison of operative and nonoperative groups. We commend the Swedish lumbar spine study group and their remarkable efforts; they elevated the sophistication of spine research and spawned many more excellent works to help settle the ongoing controversy on the ideal treatment of low back pain.

Background: Numerous preclinical and clinical studies have reported on the use of platelet concentrates to promote tissue healing. The results in spinal fusion applications are limited and controversial., Purpose: The purpose of the current prospective clinical cohort study is to assess the effect of Autologous Growth Factors (AGF) on lumbar interbody fusion with specific attention paid to determination of clinical and radiographic outcomes., Study Design/setting: Prospective clinical study, Patient Sample: Candidates for anterior-posterior lumbar fusion with diagnosis of degenerative disc disease and/or up to grade I spondylolytic spondylolisthesis based on positive provocative discography., Outcome Measures: Clinical (visual analogue pain scale/functional outcome assessment) and radiographic outcomes (fusion on computed tomography at 6 months and plain radiographs at 12 and 24 months)., Methods: Thirty-seven patients were assigned to standard anterior-posterior interbody fusion L2-S1 (single or two-level) using iliac crest bone graft (autograft group: 22 patients with 32 levels operated) or allograft combined with autogenous growth factors (AGF group: 15 patients with 25 levels operated). Radiographic outcomes were collected at 6 months postsurgery with computed tomography and at 12 and 24 months with plain radiographs. Pre- and postoperative clinical outcome measures included visual analog scores (VAS) for back and leg pain (0-10), SF-36 scores, and Oswestry disability determination. Average clinical and radiographic follow-up for the autograft group was 24.3+/-5.6 months (12-36 months) and AGF was 25.7+/-7.5 (6-40 months)., Results: Fusion incorporation at each end plate was determined at 56% in both autograft and AGF (p=NS) patients based on computed tomography at 6 months with minimal subsidence noted and no direct correlation between the incidence or degree of cage subsidence and bone graft technique. The 12- and 24-month radiographic results confirmed an 85% arthrodesis rate for the autograft patients, whereas the AGF patients had an 89% fusion rate (p=NS). Clinical outcomes were similar for both groups and no significant differences were noted for pain or functional outcome improvements., Conclusions: AGF combined with an allograft carrier is equivalent in radiographic and clinical outcomes to autograft in one- or two-level lumbar interbody fusion with supplemental posterior fixation and, thus, eliminates any morbidity from iliac crest bone graft harvesting. AGF combined with an appropriate carrier is a reasonable alternative to autograft and expensive bone induction technologies. Further research is still required to examine the optimum carriers, preparation and formulation, and platelet concentrations for this technology.

Background Context: The rise in spinal fusion procedures has led to an increase in the available number and variety of bone graft substitutes. As our understanding of the biologic processes that influence bony fusion has improved, appreciation for the role of the carrier material involved in bone grafts has also increased., Purpose: The abundance of products available leaves a surgeon with many choices. Knowledge of the current advances will allow for more critical review of the literature and improved decision making when choosing bone graft materials., Study Design/setting: Review of the English-language literature., Methods: A critical review of basic science, animal and human studies that investigate the types and role of carrier materials used in spine surgery., Results: The myriad of carrier material available to the spine surgeon is related to the many options in bone graft material. Allograft is an important osteoconductive agent but has its disadvantages especially in regard to disease transmission and immunogenicity. Collagen in various forms is an effective carrier for bone morphogenic protein and autogenous stem cells and can be easily combined with other bone graft materials. Synthetic options include hydroxyapatite and calcium phosphate ceramic materials with different formulations; all are osteoconductive only but can be combined with osteoinductive and/or osteogenic components. Bioabsorbable carriers are effective for use with bone morphogenic protein and can also be used in multiple forms and settings., Conclusions: Many bone graft carriers exist, and multiple studies have shown their efficacy. It appears that no one carrier is ideal but each situation might influence the choice of one carrier over another.

Objective: Anterior cervical discectomy and fusion (ACDF) is a successful procedure for the degenerative cervical spine. One goal of the fusion is to restore the loss of disc height that results from the degenerative process. Whereas cervical alignment improves with increased disc height, the ideal graft size used for disc space restoration is unknown. Few studies have examined the relationships between these changes in cervical alignment and clinical outcomes., Methods: All patients underwent a single-level ACDF at the authors' institution. Radiographs at early and final follow-up were examined, and three measurements were made: disc height, disc space angulation, and spinous process distance. These radiographic measurements were correlated with Visual Analog Scales (VASs) for neck and arm pain and Oswestry Disability Index (ODI)., Results: There were significant changes in disc height (5.3 vs 7.0 mm) as well as disc space angulation (3.3 degrees vs 0.1 degrees ). Reduction in neck pain VAS score (6.7 vs 3.2) and arm pain VAS score (5.1 vs 2.3) was significant. ODI scores were not statistically different, but improvement of 20.1% was observed. Correlations between radiographic parameters and clinical outcomes were moderate to low, and none was significant., Conclusions: While restoration of cervical alignment and disc height is important, clinical results are critical in analysis of outcomes following ACDF. We have shown that although clinical outcomes remain good, there does not appear to be any strong correlation with radiographic results. Emphasis on restoration of cervical alignment appears justified, but its influence on clinical outcomes may be overstated.

Background Context: Rheumatoid arthritis is a debilitating polyarthropathic degenerative condition. Eighty-six percent of patients with rheumatoid arthritis have cervical spine involvement. Often these lesions are clinically asymptomatic or symptoms are erroneously attributed to peripheral manifestation of the patient's rheumatoid disease. Because these lesions are common and missed diagnosis can result in death, early recognition is vital., Purpose: The purpose of this literature review is to identify common lesions present in the rheumatoid neck and review diagnostic methods as well as treatment options for those requiring surgical intervention., Study Design: A review of the English medical literature with focus on more recent studies on the presentation, diagnosis, management, surgical treatment and clinical outcomes of rheumatoid arthritis of the cervical spine., Methods: A comprehensive literature review of the English medical literature obtained through Medline up to November 2003 was performed identifying relevant and more recent articles that addressed the presentation, evaluation, surgical management and outcomes of rheumatoid patients with cervical spine involvement., Results: If left untreated, a large percentage of rheumatoid patients with cervical spine involvement progress toward complex instability patterns resulting in significant morbidity and mortality. Once myelopathy occurs, prognosis for neurologic recovery and long-term survival is poor. In properly selected patients, anterior and/or posterior cervical procedures can prevent neurologic injuries and preserve remaining function., Conclusion: Cervical spine involvement in the rheumatoid patient is common and progressive. Early diagnosis and treatment is imperative; however, surgical intervention should be considered carefully because associated morbidity and mortality is high.

Study Design: Cadaveric human cervical spine anatomic study using posterior lateral mass screw-rod instrumentation to assess foraminal enlargement via distraction techniques., Objectives: To determine the role of posterior cervical distraction on foraminal dimensions and to ascertain the impact of this technique on segmental kyphosis., Summary of Background Data: Management of cervical spondylotic radiculopathy includes removal of offending compressive structures and enlarging the neuroforamen via anterior discectomy with interbody fusion or posterior laminoforaminotomy., Methods: Six human cervical spines were prepared and posterior exposure performed. Lateral mass screws were inserted from C5 to C7 and a longitudinal rod attached. Distraction was applied between the screw heads at 2 mm intervals and accuracy confirmed with digitized calipers. Pre- and postdistraction computed tomography was performed including axial and reformatted images. Foraminal area, height, and width and sagittal alignment and disc heights were evaluated., Results: The results suggest that minimal posterior distraction of 4 to 6 mm at C5-C6 and C6-C7 may enlarge the neuroforamen by 10 to 18 mm. Foraminal height and width increased minimally from baseline to maximum distraction; however, these measurements did not reach statistical significance at either level. A decrease of segmental lordosis at C5-C6 was noted from baseline to 8 mm of distraction. Statistically significant kyphosis from baseline was present at 6 mm of distraction leading to overall 5.2 +/- 1.4degrees change in alignment. At C6-C7, statistically significant kyphosis was not present until 8 mm of distraction (4.62 +/- 2.23degrees)., Conclusions: This study suggests that posterior cervical instrumented distraction in the setting of foraminal stenosis is a reasonable supplement to direct laminoforaminotomy and nerve root decompression. Distraction leads to minimal segmental kyphosis, allowing this technique to serve as an adjunct for additional foraminal enlargement.

Background Context: The use of rigid instrumentation combined with bone graft makes intuitive sense given the requirements for vascular ingrowth, bone formation and a stable environment for the cellular events of healing to develop. However, with the advances of potent osteoinductive growth factors, the role of internal fixation may come into question. Whether bone morphogenic proteins (BMPs) would benefit from a more "stable" spinal segment for bone production and modeling remains unknown. In addition, it is unknown whether BMP and rigid fixation may have an additive effect on fusion healing., Purpose: This study is proposed to test the hypothesis that rigid fixation in the lumbar spine would be advantageous to achieve fusion for autogenous bone grafting, but fusion would occur regardless of fixation with the use of osteogenic protein (OP)-1., Study Design/setting: A histologic and radiographic analysis of BMP in a rabbit lumbar fusion model., Methods: Thirty-two rabbits were randomized into four groups: 1) control animals: in situ posterolateral L5-L6 arthrodesis using autogenous iliac crest bone graft; 2) fixation group: posterolateral arthrodesis L5-L6 with autogenous bone graft and interspinous fixation; 3) OP-1 group: in situ posterolateral L5-L6 arthrodesis using OP-1 and 4) combined OP-1 and fixation group. Radiographic fusion analysis was performed with computed tomography scans at 3 and 12 weeks after surgery. Decalcified histology was performed to assess tissue morphology and cellularity., Results: Minimal evidence of fusion was noted at 3 weeks with autograft or OP-1. By 12 weeks, all OP-1-treated animals had solid fusion, whereas no fusion was noted in autograft animals. The addition of fixation slightly increased radiographic fusion at 3 weeks in autograft and OP-1 groups but did not affect OP-1 animals at 12 weeks where all were fused. Decalcified histologic results confirmed the proliferative bone formation noted with OP-1 and the variable cellular response with autograft., Conclusions: The results of the present study suggest that the osteoinductive effect of OP-1 may be only minimally enhanced early in the bone healing process but does not appear to be affected in the long term by spinal fixation in the rabbit intertransverse fusion model. Fixation appeared to enhance early fusion in the autograft group.

This study provides clinical and radiographic information and characteristics that may best define the presence of significant lumbar foraminal stenosis and reports on the outcome of surgical intervention. Although anatomy of the lumbar intervertebral foramen (including static and dynamic pathologic compression of the exiting nerve root) has been described, few studies have focused on the clinical and radiographic features of foraminal stenosis requiring surgical intervention. We retrospectively studied 65 patients with lumbar foraminal stenosis for presenting clinical and radiographic features and intraoperative findings. Symptoms included leg and back pain (100%), paresthesias (45%), and subjective weakness (31%). Examination revealed lumbar tenderness (71%), limited lumbar extension (57%), focal motor weakness (48%), and positive tension signs (42%). The L5 nerve root was most often involved (75%). Almost 50% of patients had already undergone spinal decompression surgery. Surgical procedures included laminectomy and foraminotomy (52 patients) and laminotomy and foraminotomy (23 patients). A concomitant arthrodesis was performed in 63 patients. There were 29 excellent, 25 good, 6 fair, and 5 poor results based on a modified outcome scale at 32.5-month follow-up. Findings suggest that foraminal stenosis is a frequent cause of persistent symptoms after surgery, is most common at the lumbosacral junction, is best identified on parasagittal magnetic resonance images or on images reconstructed with computed tomography, and may be static or dynamic in etiology.

The authors performed a prospective study of 63 patients with cervical radiculopathy treated with Robinson anterior cervical discectomy and fusion and compared the traditional or standard and reverse graft techniques. Modifications of the standard Robinson grafting techniques have been proposed. The reverse graft technique has theoretical advantages, including limiting the deleterious effects of graft extrusion and maintaining rigid middle column support. A radiographic evaluation and an assessment of clinical outcome based on the criteria of Odom were performed prospectively for as long as 1 year after surgery. Thirty-one patients were treated with the standard grafting technique and 32 with the reverse graft orientation. The radiographic evaluation showed no significant differences between the two techniques with regard to sagittal alignment and disk heights. The overall fusion grade was higher in the reverse graft technique (p < 0.05). There were 93% and 96% good to excellent results in the standard graft and reverse graft groups, respectively. The authors report no significant differences associated with the standard or reverse anterior cervical grafting techniques in terms of radiographic alignment or disk height loss over time or at early clinical outcome. However, improved fusion grade was noted with the reverse graft technique, which may be related to end plate and intervertebral space preparation. The reverse grafting technique is an acceptable alternative to the standard graft orientation.

Neck pain can originate from any number of factors. Perhaps the most difficult symptom complex to resolve is axial neck pain arising from upper cervical nerve root compression. The purpose of this study is to report the results of surgical intervention in a series of patients with neck pain from C4 radiculopathy. Twelve consecutive patients who were diagnosed with C4 radiculopathy were retrospectively reviewed (follow-up, 22+/-16.3 months). Patients underwent either anterior cervical discectomy and fusion or posterior laminoforaminotomy at the C3-C4 segment. The results show that a good to excellent clinical result can be achieved in most patients (92% in our series). The importance of identifying patients with C4 radiculopathy lies in the fact that surgery can alter the natural history of neck pain secondary to upper cervical root radiculopathy, unlike axial neck pain from degenerative disk disease.

The purpose of this prospective study was to compare the effect of adjunctive direct current (DC) electrical stimulation and pulsed electromagnetic field therapy (PEMF) on augmentation of instrumented lumbar fusion. Sixty-one patients undergoing lumbar spine fusion were enrolled in the study and randomized to one of three treatment protocols: 1) adjunctive PEMF group (n = 22) fitted with Spinal-Stim model 8212(AME) within 30 days of surgery; 2) DC group (n = 17) had a SpF-2T stimulator(EBI) implanted at the time of surgery; or 3) control group (n = 22). The fusion mass bone mineral density (BMD) assessment was performed on 3-month and 1-year radiographs for each patient. Lateral flexion-extension and anteroposterior radiographs were evaluated at 1 year to determine the presence of fusion. Clinical outcome patient analyses were performed at 1 year. At 1-year follow-up, radiographic fusion and fusion mass bone density were not significantly different among the groups. In the nonstimulated group, there were 43% excellent, 43% good, and 14% fair results. In the PEMF group, there were 35% excellent, 50% good, 10% fair, and 5% poor results. In the DC group, there were 32% excellent, 37% good, and 31% fair results. The results of the current study suggest that electrical stimulation does not significantly enhance fusion rate in instrumented lumbar arthrodesis, although we observed a statistically insignificant trend toward increased fusion mass BMD in the electrically stimulated groups. The significance of increased BMD remains unknown.

Lumbar foraminal stenosis is an important pathologic entity to identify in the patient being treated for radicular symptoms. This update reviews the anatomy, clinical presentation, neuroradiographic evaluation, and treatment of pathology located in the intervertebral foramen. Patients with significant leg pain refractory to conservative treatment and concordance between the demonstrated area of stenosis and radicular symptoms and signs are candidates for the decompressive procedures discussed. The role of arthrodesis and spinal instrumentation in the management of foraminal stenosis also is addressed.

As an aid to the assessment of alignment and lordosis, four contour lines can be drawn on the lateral radiograph of the cervical spine. One of these contour lines is the posterior vertebral contour line, in which a smooth, gentle curve, convex anteriorly, is formed by a line drawn along the posterior margins of the cervical vertebral bodies. It is unknown whether discontinuity in the posterior contour line at this level represents a pathologic process of the odontoid. We analyzed the posterior cortex of C-2 and the odontoid in 500 lateral cervical spine radiographs to determine the amount of step-off (deviation from the posterior contour line) seen in normal lateral cervical roentgenograms. Only 15% (n = 75) showed any step-off; none exceeded 3 mm. We recommend that patients presenting with a history of cervical spine trauma who have a step-off at the posterior contour line at the odontoid/C-2 level of > or =3 mm should have fine-cut tomography or multiplanar computed tomography scanning to further assess the odontoid process and rule out fracture.

The treatment of cervical metastatic disease requires a multidisciplinary team approach to evaluation and management and demands consideration of multiple factors before a regimen is accepted. The patient's overall functioning and medical status, life expectancy, history of treatment, tumor type, and location within the cervical spine and individual vertebrae all must be evaluated carefully. The majority of lesions will be amenable to nonoperative aggressive modalities aimed at shrinking tumor size and halting growth. Surgical intervention is limited to specific indications, including spinal instability, progressive neurologic deterioration from bony collapse and compression, intractable pain, and failure of conservative means of treatment.

Cross-sectional studies have demonstrated significant decreases in bone mass in femoral cortical bone adjacent to prostheses. Thirty-six patients who had undergone 31 cemented and 9 uncemented primary total hip arthroplasties (THA) were prospectively studied to define further the natural history of this femoral cortical bone loss. Dual-energy X-ray absorptiometry (DXA) was employed to quantify bone mineral density (BMD) changes in four subregions around the femoral prostheses. Femoral BMD loss (average 12.3%) was observed in the three proximal subregions 2 months postoperatively. This loss increased to 21.2% by 6 months postoperatively, and by 2 years postoperatively it averaged 25.5% in the same three subregions. There were no significant BMD changes in the subregion distal to the prosthesis tip or in the contralateral hip. Subgroups were compared based on prosthesis size and cement use. Statistically significant differences in BMD loss were observed between the large cemented cobalt chrome prosthesis group (n = 8) and the large uncemented titanium prosthesis group (n = 8). These differences were only present in the most proximal medial subregion where the large cemented groups had twice the bone loss in this area as compared with the large uncemented group. The data indicate that bone loss occurs adjacent to femoral prosthesis within 2 months of surgery and that DXA is a useful technique to quantify prospectively femoral cortical bone loss following THA.

Cervical spine fracture/dislocations without neurologic compromise are rare. We report the case of a complete fracture/dislocation from C-5 to C-6 with neurologic sparing and discuss the biomechanical pathogenesis and treatment of this injury.

We have previously shown that calcitonin (CT), an inhibitor of bone resorption, increases vertebral, but not femoral bone density in the rat. To address the physiologic responses associated with these effects on bone mineral density (BMD), we assessed mRNA transcripts reflecting activities of osteoblasts (type I collagen, osteocalcin, osteopontin, and alkaline phosphatase), osteoclasts [tartrate-resistant acid phosphatase (TRAP)], and cell proliferation (histone H4) in the spine and femur of these rats. CT increased spine BMD while increasing type I collagen and decreasing TRAP and histone mRNAs. In the femur, where CT had no effect on BMD, it decreased type I collagen and histone H4 mRNA but did not affect TRAP. CT had no effect on the gene expression of osteocalcin, osteopontin, or alkaline phosphatase at either site. The results indicate that selective alterations in gene expression, as reflected by steady state mRNA levels, are consistent with the changes observed by BMD measurement, and can more clearly define the specific contribution from osteoblast and osteoclast activity. This study demonstrates a heterogeneity in response of the axial and appendicular skeleton to CT, reflected by alterations in gene expression that provide a basis for understanding the observed BMD responses to various pharmacologic interventions.

Study Design: The authors report a patient with delayed inferior thyroid artery pseudoaneurysm after uneventful anterior cervical discectomy and fusion., Methods: The Smith-Robinson approach to the anterior cervical spine is a commonly used and relatively safe surgical approach for cervical disc disease., Results: This case is unusual in two respects: 1) the vascular complication occurred 9 days postoperatively; and 2) the inferior thyroid artery was embolized without the need for immediate exploration and surgical ligation., Conclusion: The patient was successfully managed with therapeutic embolization.

TSH-suppressive doses of thyroid hormone are associated with bone loss. We have previously reported that L-T4 decreases femoral, but not vertebral bone mineral density (BMD) in rats. As bisphosphonates are able to decrease bone resorption, especially in high bone turnover states, we investigated the potential effects of etidronate disodium (EHDP) on L-T4-induced bone loss in the rat model by assessing BMD and gene expression of osteoblast (osteocalcin, osteopontin, type I collagen, and alkaline phosphatase), osteoclast (tartrate-resistant acid phosphatase), and cell growth (histone) markers in the skeleton. L-T4 administered for 20 days decreased BMD in the femur, but had no effect on the lumbar spine. EHDP alone had no effect on femoral or vertebral BMD, but did prevent the L-T4-induced bone loss in the femur. L-T4 increased mRNA levels of alkaline phosphatase, tartrate-resistant acid phosphatase, and histone H4 in the femur, but not in the vertebrae. EHDP, which alone had no effect on gene expression in the femur or vertebrae, inhibited the effect of L-T4 on mRNA markers in the femur. The results demonstrate that EHDP can prevent the L-T4-induced decrease in femoral BMD in rats that is associated with the prevention of changes in mRNA markers of osteoclast and osteoblast function. EHDP and other bisphosphonate compounds may be useful in the prevention of thyroid hormone-induced bone loss in humans.

1 alpha,25-Dihydroxyvitamin D3 exerts rapid nongenomic effects on rat osteoblast-like cells independent of the classic nuclear receptor. These effects include changes in phospholipid metabolism and cell calcium. Intracellular calcium itself has been proposed to regulate intracellular pH in osteoblast cell lines. The purpose of this study was to determine the effect of 1 alpha,25-dihydroxyvitamin D3 on intracellular pH, the relationship of changes in calcium to changes in pH, and the role of pH changes in genomic activation. 1 alpha,25-Dihydroxyvitamin D3 increased intracellular pH within 10 min in rat osteoblast-like cells, an effect that was inhibited by removal of extracellular sodium and by the biologically inactive epimer 1 beta,25-dihydroxyvitamin D3. The hormone increased intracellular calcium in Quin 2 loaded cells in the presence and absence of extracellular sodium. The 1 alpha,25-dihydroxyvitamin D3-induced increments in osteocalcin and osteopontin mRNA levels were abolished in sodium-free medium. The results indicate that 1 alpha,25-dihydroxyvitamin D3-induced increments in cellular calcium precede cell alkalinization and that these changes in intracellular pH may modulate steady-state mRNA levels of genes induced by vitamin D.

Gallium nitrate (GN) is an inhibitor of bone resorption and thereby may result in a change in coupled bone formation. In the present investigation the effects of GN on bone formation were studied in the rat osteosarcoma (ROS) 17/2.8 cell line and normal diploid rat osteoblasts (ROB) in vitro and the femur of rats treated in vivo, measuring mRNA levels for two osteoblast parameters, type I collagen, a marker of matrix formation, and osteocalcin, a bone specific protein and also histone H4, a marker of cell proliferation. GN, at 50 microM for 3 h, increased type I collagen mRNA levels by 132% in ROS 17/2.8 cells and by 122% in proliferating ROB cells. Osteocalcin (OC) mRNA levels were decreased by 61% in ROS 17/2.8 cells and by 97% in differentiated ROB cells. These changes occurred in the absence of any effects on cell proliferation. Seventy-day-old female rats were then treated with GN, 0.5 mg/kg/day, for 3 weeks. As previously reported, GN decreased serum calcium levels, but had no effect on lumbar or femoral bone density. In contrast to the in vitro effects, GN had no effect on type I collagen steady-state mRNA levels in the femur; however, it decreased OC steady-state mRNA levels in the femur by 58%. These results suggest that GN has similar in vitro effects in transformed and normal osteoblasts, while the collagen-stimulatory effects observed in vitro cannot be extrapolated to in vivo models. The consistent inhibition of osteocalcin in vitro and in vivo suggests a more specific target for GN that may relate to its effects in inhibiting bone resorption in normal rats.

Our previous studies have demonstrated the production and release of a tumor-derived factor that promoted lipolysis in normal adipocytes. We further demonstrated that this in vitro lipolysis was correlated with the in vivo loss of total carcass lipids induced by the presence of the same tumor. This study identified and isolated this "lipolysis-promoting" factor (LPF), released into the extracellular environment (conditioned media) by the human A375 melanoma cell line, which appears to be responsible for the previously demonstrated induction of in vitro and in vivo lipolytic activity. Unlike previously described non-tumor-derived molecules, such as tumor necrosis factor-alpha/cachectin, which have been implicated in cancer cachexia, the LPF induces alterations in lipid metabolism similar to those observed in cancer patients. The biochemical nature of human tumor-derived LPF appears to be a heat-stable molecule with an apparent molecular weight of approximately 6000. The lipolysis-promoting activity was trichloroacetic acid precipitable, but not precipitable with protamine sulfate or extractable with chloroform:methanol. Its activity appears to be resistant to enzymatic treatments with protease K, trypsin, Pronase, RNase, and DNase, as well as to periodate oxidation. Immunochemically, LPF appears to be distinct from tumor necrosis factor-alpha/cachectin. Furthermore, in contrast to the mechanism of action of tumor necrosis factor-alpha/cachectin, the mechanism of "lipolysis promotion" by LPF appears to be by the induction of cellular lipase activity.