Takashi Namikawa

Characteristic Radiographic or Magnetic Resonance Images of Fresh Osteoporotic Vertebral Fractures Predicting Potential Risk for Nonunion: A Prospective Multicenter Study

Study Design. Prospective multicenter study. Objective. To identify radiographic or magnetic resonance (MR) images of fresh vertebral fractures that can predict a high risk for delayed union or nonunion of osteoporotic vertebral fractures (OVFs). Summary of Background Data. Vertebral body fractures are the most common fractures in osteoporosis patients. Conservative treatments are typically chosen for OVFs, and associated back pain generally subsides within several weeks with residual persistent deformity of the vertebral body. In some patients, OVF healing is impaired and correlated with prolonged back pain. However, assessments such as plain radiograph or MR images taken during the early phase to predict high risks for nonunions of OVFs and/or poor prognoses have not been identified. Methods. A total of 350 OVF patients from 25 institutes were enrolled in this clinical study. Plain radiograph and MR images of the OVFs were routinely taken at enrollment at the respective institutes. The findings on the plain radiograph and MR images were classified after enrollment in the study. All the patients were treated conservatively without any surgical intervention. After a 6-month follow-up, the patients were classified into two groups, a union group and a nonunion group, depending on the presence of an intravertebral cleft on plain radiograph or MR images. The associations of the images from the first visit with those of the corresponding nonunions at the 6-month follow-up were analyzed by multivariate logistic regression to elucidate specific image characteristics that may predict a high risk for nonunion of OVFs. Results. Forty-eight patients (49 vertebrae) among the 350 patients (363 vertebrae) were classified as nonunions, indicating a nonunion incidence of 13.5% for conventional conservative treatments for OVFs. The statistical analyses revealed that a vertebral fracture in the thoracolumbar spine, presence of a middle-column injury, and a confined high intensity or a diffuse low intensity area in the fractured vertebrae on T2-weighted MR images were significant risk factors for nonunion of OVFs. Conclusion. The results of this study revealed significant relationships between plain radiograph and MR images of acute phase OVFs and the incidence of nonunion. As these risk factors are defined more clearly and further validated, they may become essential assessment tools for determining subsequent OVF treatments. Patients with one or more of the earlier-described risk factors for nonunion should be observed carefully and provided with more intensive treatments.

Experimental Spinal Fusion With Recombinant Human Bone Morphogenetic Protein-2 Delivered by a Synthetic Polymer and β-Tricalcium Phosphate in a Rabbit Model

Study Design. An experimental animal study to achieve posterolateral intertransverse process spine fusion with recombinant bone morphogenetic protein in combination with a new delivery system. Objective. To evaluate the efficacy of a new synthetic biodegradable bone-inducing material containing recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone-graft substitute for posterolateral intertransverse process fusion in a rabbit model. Summary of Background Data. rhBMP-2, a powerful bone-inducing cytokine, has been used as a bone graft substitute in combination with animal-derived collagen to achieve spinal fusion in animal models. However, the minimum dose of rhBMP-2 required to obtain solid posterolateral intertransverse process fusion was high on the basis of previous reports (>100 &mgr;g in rabbit models). To improve the efficacy, performance of rhBMP-2, and the safety of the delivery system for this protein, a more sophisticated system is required. Methods. To fabricate one implant for one-side L4–L5 intertransverse process fusion, &bgr;-tricalcium phosphate (&bgr;-TCP) powder (300 &mgr;g), a polymer gel (PLA-DX-PEG block copolymer; 300 &mgr;g) and rhBMP-2 (7.5, 15, or 30 &mgr;g) were mixed and manually shaped to resemble a rod. Through a posterolateral approach, two implants were placed on both sides (1 per side) by surgery so as to bridge the transverse processes of adult New Zealand white rabbits (n = 27). In control animals, implants without rhBMP or autogenous cortico-cancellous bone chips from the iliaccrest were placed in a similar location. The lumbar vertebrae were recovered 6 weeks after surgery. The posterolateral fusion was examined by manual palpation, radiography, biomechanical testing, and histology. Results. Rabbits that received 15 or 30 &mgr;g of rhBMP-2 showed consistent fusion. However, solid fusion was seen in 2 of 5 rabbits with autografting and rabbits that received 7.5 &mgr;g of rhBMP-2. Fusion was not observed in the rabbits that did not receive rhBMP-2. Conclusions. Consistent spinal fusion was obtained by implanting a biodegradable bone-inducing implant composed of &bgr;-TCP, PLA-DX-PEG, and rhBMP-2 within a period of 6 weeks. The rhBMP-2 doses required for the spinal fusion were significantly lower than those reported previously.

Enhancing effects of a prostaglandin EP4 receptor agonist on recombinant human bone morphogenetic protein-2 mediated spine fusion in a rabbit model.

Study Design. An experimental animal study aimed at achieving posterolateral intertransverse process fusion with rhBMP-2 in combination with the local delivery of an EP4 receptor agonist. Objective. To determine whether an EP4 receptor agonist (EP4A) can reduce the amount of BMP required to achieve posterolateral spinal fusion in rabbits. Summary of Background Data. In the clinic, BMP retaining implants are used for spinal fusion and the treatment of pseudarthrosis after long bone fracture. However, the requirement of high doses of BMP-2 for bone formation in humans makes the implants expensive and limits their use in the clinic. Previous studies in our laboratory using a new delivery system involving a synthetic polymer/&bgr;-TCP powder composite had shown it was possible to reduce the total BMP-2 amount to 30 &mgr;g per fusion in a rabbit model. To further reduce the dose of BMP required for a successful fusion, we explored the use of a chemical compound to enhance the bone-inducing action of BMP-2. Methods. In order to prepare 1 implant to bridge the unilateral L5 and L6 transverse processes, 300 mg of polymer gel (PLA-DX-PEG block copolymer), 300 mg of &bgr;-TCP powder, rhBMP-2 (7.5, 3.75, or 0 &mgr;g), with or without EP4A (45 &mgr;g) were mixed and manually shaped to resemble a rod. Through a posterolateral approach, 2 implants were placed on both sides (1 per side) by surgery in order to bridge the transverse processes of adult New Zealand white rabbits (n = 48). The lumbar vertebrae were recovered 6 weeks after surgery. The posterolateral fusion was examined by manual palpation, radiography, biomechanical testing, and histology. Results. All of 8 rabbits that received 7.5 &mgr;g of BMP-2 and EP4A consistently showed fusion by significant amount of new bone formation. However, solid fusion was seen in only 3 of 8 rabbits that received 7.5 &mgr;g of BMP-2 without the EP4 receptor agonist. Conclusion. Local administration of an EP4 receptor agonist enhanced the bone-inducing activity of BMP-2 in a rabbit posterolateral lumbar spinal fusion model and as a result, the dose of BMP-2 required for this outcome was reduced by 50% compared with our previous report. The coadministration of this compound via a local delivery system may help to reduce the costs of spine fusion with use of BMP-2 in the clinic.

Repair of long intercalated rib defects in dogs using recombinant human bone morphogenetic protein‐2 delivered by a synthetic polymer and beta‐tricalcium phosphate

Long intercalated defects in canine ribs can be repaired successfully using porous beta-tricalcium phosphate (beta-TCP) cylinders, infused with a biodegradable polymer (poly D,L-lactic acid-polyethylene block copolymer) containing recombinant human bone morphogenetic protein-2 (rhBMP-2). We previously reported the successful regeneration of bony rib and periosteum defects using beta-TCP cylinders containing 400 microg of rhBMP-2. To reduce the amount of rhBMP-2 and decrease the time required for defect repair, we utilized a biodegradable polymer carrier, in combination with rhBMP-2 and the porous beta-TCP cylinders. An 8 cm long section of rib bone was removed and replaced with an implant comprised of the porous beta-TCP cylinders and the polymer containing 80 microg of rhBMP-2. Six weeks after surgical placement of the beta-TCP cylinder/polymer/BMP-2 implants, new rib bone with an anatomical configuration and mechanical strength similar to the original bone was regenerated at the defect site. The stiffness of the regenerated ribs at 3, 6, and 12 weeks after implantation of the composite implant was significantly higher than that of ribs regenerated by implantation of rhBMP-2/beta-TCP implants. Thus, addition of the synthetic polymer to the drug delivery system for BMP potentiated the bone-regenerating ability of the implant and enabled the formation of mechanically competent rib bone. This new method appears to be applicable to the repair of intercalated long bone defects often encountered in clinical practice.

The influence of approach side on facet preservation in microscopic bilateral decompression via a unilateral approach for degenerative lumbar scoliosis. Clinical article.

OBJECT The authors compared the clinical outcomes of microscopic bilateral decompression via a unilateral approach (MBDU) for the treatment of degenerative lumbar scoliosis (DLS) and for lumbar canal stenosis (LCS) without instability. The authors also compared postoperative spinal instability in terms of different approach sides (concave or convex) following the procedure. METHODS The authors retrospectively reviewed data obtained in 50 consecutive patients (25 in the DLS group and 25 in the LCS group) who underwent MBDU; the minimum follow-up period was 2 years. Patients with DLS were divided into 2 subgroups according to the surgical approach side: a concave group (23 segment) and a convex group (17 segments). The Japanese Orthopaedic Association Scale scores for the assessment of low-back pain were evaluated before surgery and at final follow-up. The Japanese Orthopaedic Association Scale scores and recovery rates were compared between the DLS and LCS groups, and between the convex and concave groups. Cobb angle and scoliotic wedging angle (SWA) were evaluated on standing radiographs before surgery and at final follow-up. Facet joint preservation (the percentage of preservation) was assessed on pre- and postoperative CT scans, compared between the LCS and DLS groups, and compared between the concave and convex groups. The influence of approach side on postoperative progression of segmental instability was also examined in the DLS group. RESULTS The mean recovery rate was 58.7% in the DLS and 62.0% in the LCS group. The mean recovery rate was 58.6% in the convex group and 60.6% in the concave group. There were no significant differences in recovery rates between the LCS and DLS groups, or between the DLS subgroups. The mean Cobb angles in the DLS group were significantly increased from 12.7° preoperatively to 14.1° postoperatively (p < 0.05), and mean preoperative SWAs increased significantly from 6.2° at L3-4 and 4.1° at L4-5 preoperatively to 7.4° and 4.9°, respectively, at final follow-up (p < 0.05). There was no significant difference in percentage of preservation between the DLS and LCS groups. The mean percentages of preservation on the approach side in the DLS group at L3-4 and L4-5 were 89.0% and 83.1% in the convex group, and those in the concave group were 67.3% and 77.6%, respectively. The percentage of preservation at L3-4 was significantly higher in the convex than the concave group. The mean SWA had increased in the concave group (p = 0.01) but not the convex group (p = 0.15) at final follow-up. CONCLUSIONS The MBDU can reduce postoperative segmental spinal instability and achieve good postoperative clinical outcomes in patients with DLS. The convex approach provides surgeons with good visibility and improves preservation of facet joints.

Prognostic Factors for Reduction of Activities of Daily Living Following Osteoporotic Vertebral Fractures

Study Design. Prospective cohort study. Objective. To elucidate the prognostic factors indicating reduced activities of daily living (ADL) at the time of the 6-month follow-up after osteoporotic vertebral fracture (OVF). Summary of Background Data. OVF has severe effects on ADL and quality of life (QOL) in elderly patients and leads to long-term deteriorations in physical condition. Many patients recover ADL with acceleration of bony union and spinal stability, but some experience impaired ADL even months after fracture. Identifying factors predicting reduced ADL after OVF may prove valuable. Methods. Subjects in this prospective study comprised 310 OVF patients from 25 institutes. All patients were treated conservatively without surgery. Pain, ADL, QOL, and other factors were evaluated on enrollment and at 6 months. ADL were evaluated using the criteria of the Japanese long-term care insurance system to evaluate the degree of independence. We defined reduced ADL as a reduction of at least single grade at 6 months after fracture and investigated factors predicting reduced ADL after OVF, using uni- and multivariate regression analysis. Results. ADL were reduced at 6 months after OVF in 66 of 310 patients (21.3%). In univariate analysis, age more than 75 years (P = 0.044), female sex (P = 0.041), 2 or more previous spine fractures (P = 0.009), presence of middle column injury (P = 0.021), and lack of regular exercise before fracture (P = 0.001) were significantly associated with reduced ADL. In multivariate analysis, presence of middle column injury (odds ratio [OR], 2.26; P = 0.022) and lack of regular exercise before fracture (OR, 2.49; P = 0.030) were significantly associated with reduced ADL. Conclusion. These results identified presence of middle column injury of the vertebral body and lack of regular exercise before fracture as prognostic factors for reduced ADL. With clarification and validation, these risk factors may provide crucial tools for determining subsequent OVF treatments. Patients showing these prognostic factors should be observed carefully and treated with more intensive treatment options.

Impact of initial conservative treatment interventions on the outcomes of patients with osteoporotic vertebral fractures.

Study Design. Prospective multicenter study. Objective. To examine whether initial conservative treatment interventions for osteoporotic vertebral fractures (OVF) influence patient outcomes. Summary of Background Data. OVFs have been described as stable spinal injuries and, in most cases, are managed well with conservative treatment. However, systematic treatments for OVF have not been clearly established. Methods. A total of 362 patients with OVF (59 males and 303 females; mean age, 76.3 yr) from 25 institutes were enrolled in this clinical study. All the patients were treated conservatively without any surgical interventions. The patient outcomes were evaluated 6 months after the fractures on the basis of Short Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS), activities of daily living (the Japanese long-term care insurance system), back pain (visual analogue scale), cognitive status (mini-mental state examination), and vertebral collapse, which were used as response variables. Furthermore, brace type, hospitalization, bisphosphonates after injury, and painkillers after injury were explanatory variables for the treatment interventions. To evaluate the independent effects of treatment interventions on patient outcomes, we performed multivariate logistic regression analyses and obtained odds ratios that were adjusted for the potential confounding effects of age, sex, level of fracture, presence of middle-column injury, pain visual analogue scale at enrollment, mini-mental state examination score at enrollment, and previous use of steroids. Results. There was no significant difference for treatment intervention factors including brace type, hospitalization, bisphosphonates after injury, and painkillers after injury. For adjusting factors, the presence of middle-column injury was significantly associated with SF-36 PCS ⩽ 40, reduced activities of daily living, prolonged back pain, and vertebral collapse. Female sex and advanced age were associated with SF-36 PCS ⩽ 40. Low mini-mental state examination scores at enrollment were associated with SF-36 PCS ⩽ 40 and reduced activities of daily living. The previous use of steroids was associated with SF-36 MCS ⩽ 40, prolonged back pain, and vertebral collapse. No other examined variables were significant risk factors for patient outcomes. Conclusion. These results showed that treatment intervention factors did not affect patient outcomes 6 months after OVF. Middle-column injury was a significant risk factor for both clinical and radiological outcomes. In the future, establishing systematic treatments for cases with middle-column injuries is needed. Level of Evidence: 2

Regenerative repair of long intercalated rib defects using porous cylinders of beta-tricalcium phosphate: an experimental study in a canine model.

Background: In maxillofacial, spinal, and orthopedic surgery, bony ribs have been used as a source of donor bone. The resultant defects are not usually repaired, despite the pain or cosmetic morbidity experienced by the patient. The authors evaluated the efficacy of an osteoconductive &bgr;-tricalcium phosphate and the contribution of the periosteum in rib bone regeneration. Methods: Two 8-cm-long intercalated rib defects were generated in each of 30 beagle dogs. In the first group (n = 15), one defect was implanted with 16 small, short, porous &bgr;-tricalcium phosphate cylinders that were connected with a titanium wire, and the other defect was left untreated. In the remaining 15 dogs, the periosteum was devitalized by ethanol, and then the same surgical procedures were performed. Each group was subdivided into three groups (n = 5), and the animals were euthanized at 3, 6, and 12 weeks. Bone regeneration was assessed radiologically, histologically, and mechanically. Results: In the defect implanted with &bgr;-tricalcium phosphate on intact periosteum, newly formed bone was present on and in the &bgr;-tricalcium phosphate cylinders and bridged both ends of the resected ribs at 12 weeks, with replacement of &bgr;-tricalcium phosphate by new bone. Mechanical testing of these ribs revealed that they had 70 percent of the strength of normal ribs when compared in a bending stress test at 12 weeks after surgery. No regenerative bone bridging the rib defects was seen in the ethanol-devitalized or untreated groups. Conclusions: Porous &bgr;-tricalcium phosphate cylinders placed in tandem on the intact periosteum might be useful for the repair of rib bone donated at surgery, presenting a new and unique method for regenerating rib defects.

Reconstruction of bone defects using rhBMP-2-coated devitalized bone.

Massive bone defects often are caused by radical resection of bone tumors. Reconstruction of the defect by reimplantation of the resected bone segment after it has been devitalized is advantageous because of its ability to match the size of the defect. In addition, this technique carries a low risk for local recurrence of the tumor, avoids immunologic reaction, and is low in cost. However, limited osteogenic potential of the devitalized bone often leads to delayed union, gradual resorption, and mechanical weakness of the reimplanted segment. We applied rhBMP-2 in a biodegradable polymer delivery system to the devitalized bone. Middiaphyseal bone defects were created by resection in rat femurs. The resected segments were autoclaved at 135°C for 15 minutes, coated with a rhBMP-2-retaining paste on the outer surface, and then reimplanted into the defects. In a brief time, newly formed bone was seen on the surface of the devitalized bone. After 12 weeks, a solid bone mass encasing the dead bone segments was consistently formed and abundant new bone formation was visible in the segments as they were remodeled. The amount of new bone formed could be regulated by the amount of the rhBMP-2-retaining paste applied to the bone segments. This method presents a new approach for the reconstruction of bone defects.

Clinical Outcomes of Posterior Lumbar Interbody Fusion for Patients 80 Years of Age and Older with Lumbar Degenerative Disease: Minimum 2 Years' Follow-Up

Study Design Retrospective study. Objective To compare clinical outcomes, radiographic evaluations including bony union rate and incidence of osteoporotic vertebral fractures (OVFxs), and perioperative complications following posterior lumbar interbody fusion (PLIF) between patients ≥80 years of age and those <80 years. Methods Ninety-six patients ≥70 years old who underwent PLIF were reviewed. We divided the patients into the two age groups, ≥80 group (n = 19) and <80 group (n = 77), and compared the clinical outcomes using Japanese Orthopaedics Association (JOA) scores and the Short-Form Health Survey (SF-36). We also evaluated bony union and the incidence of OVFxs in the both groups. Results The JOA score improved 47.6% in the ≥80 group and 49.1% in the <80 group. There were no significant differences between the two groups. Only the bodily pain component of the SF-36 improved significantly in the ≥80 group, and seven of eight components (exception was general health) improved significantly in the <80 group. Bony union rate was significantly superior in the <80 group (94.8%) compared with that of the ≥80 group (73.7%, p = 0.013). OVFx prevalence and incidence were not significantly different between the two groups, although postoperative OVFx worsened the JOA score improvement in the ≥80 group (38.8%, p = 0.02). Conclusions The present study indicated that surgical outcomes of PLIF in patients ≥80 years were comparable to those < 80 years. However, bony union rate was significantly lower and postoperative OVFx worsened the clinical outcomes in patients ≥80 years.