Incidence and risk of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) after tooth extraction in patients with autoimmune disease.

INTRODUCTION: Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a rare but serious complication in patients receiving antiresorprtive agents (AR). However, the incidence of ARONJ after tooth extraction in patients with autoimmune disease (AID) remains unclear. The present study aimed to clarify the high-risk population of ARONJ in patients with AID. MATERIALS AND METHODS: The study population comprised 232 patients treated with AR, AID or non-AID, who had undergone dental extraction from January 2011 to September 2017. The incidence and risk factors of ARONJ were analysed retrospectively. Additionally, the relationship between ARONJ and osteoporotic fracture (OF) and AR discontinuation during dental procedures was investigated. RESULTS: Of 232 patients, 10 developed ARONJ within 1 year of dental extraction. The incidence of ARONJ in patients with AID was higher than that in non-AID patients (2.0/100 person-year vs 0.5/100 person-year; p = 0.03). Among the AID patients, RA patients had strikingly high incidence of ARONJ (3.6/100 person-year). The incidence of neither ARONJ nor OF significantly differed between patients who continued and discontinued AR in the perioperative period. CONCLUSION: Patients with AID who undergo dental extraction are at high risk of ARONJ. Discontinuation of AR would not significantly contribute to reduce the incidence of ARONJ in those patients.

Cervical myelopathy due to atraumatic odontoid fracture in patients with rheumatoid arthritis: A case series.

To highlight the risk of cervical myelopathy due to occult, atraumatic odontoid fracture in patients with rheumatoid arthritis, we retrospectively reviewed radiographic findings and clinical observations for 7 patients with this disorder. This fracture tends to occur in patients with long-lasting rheumatoid arthritis and to be misdiagnosed as simple atlantoaxial dislocation. Since this fracture causes multidirectional instability between C1 and C2 and is expected to have poor healing potential due to bone erosion and inadequate blood supply, posterior spinal arthrodesis surgery is indicated upon identification of the fracture to prevent myelopathy.

Cervical Myelopathy Caused by Non-Rheumatic Retro-Odontoid Pseudotumor: An Investigation of Underlying Mechanisms and Optimal Surgical Strategy.

STUDY DESIGN: Retrospective case-control study. OBJECTIVE: This study aimed to identify the underlying pathologies of non-rheumatic retro-odontoid pseudotumors (NRPs), which would help establish an appropriate surgical strategy for myelopathy caused by NRP. METHODS: We identified 35 patients with myelopathy caused by NRP who underwent surgery between 2006 and 2017. An age- and sex-matched control group of 70 subjects was selected from patients with degenerative cervical myelopathy. Radiographic risk factors for NRP were compared between cases and controls. We also assessed surgical outcomes following occipital-cervical (O-C) fusion, atlantoaxial (C1-2) fusion, or C1 laminectomy. RESULTS: Patients with NRP had significantly lower C1 sagittal inner diameter, C2-7 range of motion (ROM), C2-7 Cobb angle, and C7 tilt, as well as significantly higher C1-2 ROM, atlantodental interval (ADI), and C1-2 to O-C7 ROM ratio. Multivariate regression analysis revealed that ADI, C2-7 ROM, and C7 tilt were independent risk factors for NRP. Neurological recovery and pseudotumor size reduction were comparable among surgical procedures, whereas post-operative cervical spine function was significantly lower in the O-C fusion group than in the other groups. CONCLUSION: Non-rheumatic retro-odontoid pseudotumor was associated with an increase in ADI, suggesting that spinal arthrodesis surgery is a reasonable strategy for NRP. C1-2 fusion is preferable over O-C fusion because of the high prevalence of ankylosis in the subaxial cervical spine. Given that 29% of patients with NRP have C1 hypoplasia, such cases can be treated by posterior decompression alone. Our study highlights the need to select appropriate surgical procedures based on the underlying pathology in each case.

Synthetic scaffold coating with adeno-associated virus encoding BMP2 to promote endogenous bone repair.

Biomaterial scaffolds functionalized to stimulate endogenous repair mechanisms via the incorporation of osteogenic cues offer a potential alternative to bone grafting for the treatment of large bone defects. We first quantified the ability of a self-complementary adeno-associated viral vector encoding bone morphogenetic protein 2 (scAAV2.5-BMP2) to enhance human stem cell osteogenic differentiation in vitro. In two-dimensional culture, scAAV2.5-BMP2-transduced human mesenchymal stem cells (hMSCs) displayed significant increases in BMP2 production and alkaline phosphatase activity compared with controls. hMSCs and human amniotic-fluid-derived stem cells (hAFS cells) seeded on scAAV2.5-BMP2-coated three-dimensional porous polymer Poly(ε-caprolactone) (PCL) scaffolds also displayed significant increases in BMP2 production compared with controls during 12 weeks of culture, although only hMSC-seeded scaffolds displayed significantly increased mineral formation. PCL scaffolds coated with scAAV2.5-BMP2 were implanted into critically sized immunocompromised rat femoral defects, both with or without pre-seeding of hMSCs, representing ex vivo and in vivo gene therapy treatments, respectively. After 12 weeks, defects treated with acellular scAAV2.5-BMP2-coated scaffolds displayed increased bony bridging and had significantly higher bone ingrowth and mechanical properties compared with controls, whereas defects treated with scAAV2.5-BMP2 scaffolds pre-seeded with hMSCs failed to display significant differences relative to controls. When pooled, defect treatment with scAAV2.5-BMP2-coated scaffolds, both with or without inclusion of pre-seeded hMSCs, led to significant increases in defect mineral formation at all time points and increased mechanical properties compared with controls. This study thus presents a novel acellular bone-graft-free endogenous repair therapy for orthotopic tissue-engineered bone regeneration.

A retrospective study of congenital osseous anomalies at the craniocervical junction treated by occipitocervical plate-rod systems.

PURPOSE: To evaluate the effectiveness of posterior occipitocervical reconstruction using the anchors of cervical pedicle screws and plate-rod systems for patients with congenital osseous anomalies at the craniocervical junction. METHODS: Twenty patients with congenital osseous lesions who underwent posterior occipitocervical fusion using the anchors of cervical pedicle screws and plate-rod systems for reduction and fixation from 1996 to 2009 were reviewed. The lesions included os odontoideum, occipitalization of the atlas, congenital C2-3 fusion, congenital atlantoaxial subluxation, congenital basilar invagination and combined anomalies. The clinical assessment and the measurements of the images were performed preoperatively, postoperatively and at most recent follow-up. RESULTS: The combined deformity of flexion of the occipitoatlantoaxial complex and invagination of the odontoid process associated with congenital osseous lesions at the craniocervical junction was corrected by application of combined forces of extension and distraction between the occiput and the cervical pedicle screws. Preoperative myelopathy improved in 94.7% patients. The mean Ranawat value, Redlund-Johnnell value, atlantodental distance, occiput (O)-C2 angle, and C2-C7 lordosis angle improved postoperatively and was sustained at most recent follow-up. The mean cervicomedullary angle improved from 129.3° preoperatively to 153.3° postoperatively. The mean range of motion at the lower adjacent motion segment remained unchanged at most recent follow-up. The fusion rate was 95%. CONCLUSIONS: The results of the present study indicate that posterior occipitocervical reconstruction using the anchors of cervical pedicle screws and plate-rod systems is an effective technique for treatment of deformities and/or instability caused by congenital osseous anomalies at the craniocervical junction.

Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway.

A growing body of evidence suggests that immune factors that regulate osteoclast differentiation and bone resorption might be promising therapeutic agents for the treatment of osteoporosis. The expression of CLCF1, an immune cell-derived molecule, has been reported to be reduced in patients with postmenopausal osteoporosis. This suggests that it may be involved in bone remodeling. Thus, we explored the functional role of CLCF1 in osteoclastogenesis and bone loss associated with osteoporosis. Surprisingly, the administration of recombinant CLCF1 repressed excessive bone loss in ovariectomized mice and prevented RANKL-induced bone loss in calvarial mouse model. Likewise, the addition of recombinant CLCF1 to RANKL-stimulated monocytes resulted in a significant suppression in the number of differentiated osteoclasts with small resorption areas being observed on dentine slices in vitro. At the same dosage, CLCF1 did not exhibit any detectable negative effects on the differentiation of osteoblasts. Mechanistically, the inhibition of osteoclast differentiation by the CLCF1 treatment appears to be related to the activation of interferon signaling (IFN) and the suppression of the NF-κB signaling pathway. Interestingly, the expression of the main components of IFN-signaling namely, STAT1 and IRF1, was detected in macrophages as early as 1 h after stimulation with CLCF1. Consistent with these results, the blockade of STAT1 in macrophages abolished the inhibitory effect of CLCF1 on osteoclast differentiation in vitro. These collective findings point to a novel immunoregulatory function of CLCF1 in bone remodeling and highlight it as a potentially useful therapeutic agent for the treatment of osteoporosis.

One-stage posterior instrumentation surgery for the treatment of osteoporotic vertebral collapse with neurological deficits.

The number of reports describing osteoporotic vertebral fracture has increased as the number of elderly people has grown. Anterior decompression and fusion alone for the treatment of vertebral collapse is not easy for patients with comorbid medical problems and severe bone fragility. The purpose of the present study was to evaluate the efficacy of one-stage posterior instrumentation surgery for the treatment of osteoporotic vertebral collapse with neurological deficits. A consecutive series of 21 patients who sustained osteoporotic vertebral collapse with neurological deficits were managed with posterior decompression and short-segmental pedicle screw instrumentation augmented with ultra-high molecular weight polyethylene (UHMWP) cables with or without vertebroplasty using calcium phosphate cement. The mean follow-up was 42 months. All patients showed neurologic recovery. Segmental kyphotic angle at the instrumented level was significantly improved from an average preoperative kyphosis of 22.8-14.7 at a final follow-up. Spinal canal occupation was significantly reduced from an average before surgery of 40.4-19.1% at the final follow-up. Two patients experienced loosening of pedicle screws and three patients developed subsequent vertebral compression fractures within adjacent segments. However, these patients were effectively treated in a conservative fashion without any additional surgery. Our results indicated that one-stage posterior instrumentation surgery augmented with UHMWP cables could provide significant neurological improvement in the treatment of osteoporotic vertebral collapse.

Identification of IL-27 as potent regulator of inflammatory osteolysis associated with vitamin E-blended ultra-high molecular weight polyethylene debris of orthopedic implants.

Vitamin E-blended ultra-high molecular weight polyethylene (VE-UHMWPE) is a newly introduced material for prosthetic components that has proven a better mechanical performance with lesser adverse cellular responses than conventional polyethylene in experimental animal models. However, the mechanisms by which VE-UHMWPE particles trigger a reduced osteolytic activity are unclear and remain to be investigated. Therefore, the current study aims at exploring a possible anti-osteolytic mechanism associated with VE-UHMWPE particles. Transcriptional profiling and bioinformatic analyses of human macrophages stimulated by VE-UHMWPE particles revealed a distinct transcriptional program from macrophages stimulated with UHMWPE particles. Out of the up-regulated genes, IL-27 was found to be significantly elevated in macrophages cultured with VE-UHMWPE particles as compared to these with UHMWPE particles (p = 0.0084). Furthermore, we studied the potential anti-osteolytic function of IL-27 in osteolysis murine model. Interestingly, administration of recombinant IL-27 onto calvariae significantly alleviated osteolytic lesions triggered by UHMWPE particles (p = 0.0002). Likewise, IL-27 inhibited differentiation of osteoclasts (p = 0.0116) and reduced inflammatory response (p < 0.0001) elicited by conventional UHMWPE particles in vitro. This is the first study demonstrating the involvement of IL-27 in macrophage response to VE-UHMWPE particles and its regulatory role in osteolysis. Our data highlight a novel therapeutic agent for treatment of inflammatory osteolysis induced by polyethylene debris. STATEMENT OF SIGNIFICANCE: Aseptic loosening due to inflammatory osteolysis remains the major cause of arthroplasty failure and represents a substantial economic burden worldwide. Ideal approach to prevent this failure should be directed to minimize inflammatory response triggered by wear particles at the site of implant. Understanding the mechanism by which VE-UHMWPE particles triggers lesser cellular responses and reduced osteolysis as compared to conventional UHMWPE particles may aid in discovery of regulatory factors. In the current study, we reported that IL-27 is a potent regulator of inflammatory osteolysis involved in the reduced biologic activities and osteolytic potentials associated with VE-UHMWPE particles. Initiating the production IL-27 in vivo after total joint arthroplasties might be a novel strategy to prolong the life-spam of implant.

Quick and easy sample preparation without resin embedding for the bone quality assessment of fresh calcified bone using fourier transform infrared imaging.

Fourier transform infrared (FTIR) imaging is a powerful tool for the assessment of bone quality; however, it requires the preparation of thin bone sections. Conventional poly(methyl methacrylate) (PMMA) embedding for the preparation of sections takes more than two weeks and causes denaturation of the bone. Development of a quick and easy sample preparation technique without denaturation is needed for accurate clinical evaluation of fresh calcified bone using FTIR imaging. Frozen sectioning allows the quick and easy preparation of thin sections without denaturation, but it requires a substrate with good chemical resistance and improved heat shock resistance. Polypropylene (PP) film afforded both good chemical resistance and greater heat shock resistance, and the 4-µm-thick PP film coated with glue was thin enough for the IR beam to pass through it, while the optical anisotropy of infrared bands overlapping with PO43- band was negligible. The bone quality of femoral thin sections prepared by the conventional PMMA embedding and sectioning procedure (RESIN-S) or the newly developed frozen sectioning procedure (FROZEN-S) was evaluated by FTIR imaging. The mineral-to-matrix ratio and crystallinity in the RESIN-S sections were higher than those in the FROZEN-S sections, whereas the carbonate-to-phosphate ratio in the RESIN-S sections was lower than that in the FROZEN-S sections. In RESIN-S, the increased mineral-to-matrix ratio could be caused by dehydration, and the increased crystallinity and decreased carbonate-to-phosphate ratio might be consequence of dissolution of bone mineral during PMMA embedding. Therefore, the combined use of PP film coated with glue and the frozen sectioning procedure without denaturation appears well suited to the assessment of the bone quality of fresh calcified bone using FTIR imaging.

Transcriptional profile of human macrophages stimulated by ultra-high molecular weight polyethylene particulate debris of orthopedic implants uncovers a common gene expression signature of rheumatoid arthritis.

Osteolysis is a serious postoperative complication of total joint arthroplasty that leads to aseptic loosening and surgical revision. Osteolysis is a chronic destructive process that occurs when host macrophages recognize implant particles and release inflammatory mediators that increase bone-resorbing osteoclastic activity and attenuate bone-formation osteoblastic activity. Although much progress has been made in understanding the molecular responses of macrophages to implant particles, the pathways/signals that initiate osteolysis remain poorly characterized. Transcriptomics and gene-expression profiling of these macrophages may unravel key mechanisms in the pathogenesis of osteolysis and aid the identification of molecular candidates for therapeutic intervention. To this end, we analyzed the transcriptional profiling of macrophages exposed to ultra-high molecular weight polyethylene (UHMWPE) particles, the most common components used in bearing materials of orthopedic implants. Regulated genes in stimulated macrophages were involved in cytokine, chemokine, growth factor and receptor activities. Gene enrichment analysis suggested that stimulated macrophages elicited common gene expression signatures for inflammation and rheumatoid arthritis. Among the regulated genes, tumor necrosis factor superfamily member 15 (TNFSF15) and chemokine ligand 20 (CCL20) were further characterized as molecular targets involved in the pathogenesis of osteolysis. Treatment of monocyte cultures with TNFSF15 and CCL20 resulted in an increase in osteoclastogenesis and bone-resorbing osteoclastic activity, suggesting their potential contribution to loosening between implants and bone tissues. STATEMENT OF SIGNIFICANCE: Implant loosening due to osteolysis is the most common mode of arthroplasty failure and represents a great challenge to orthopedic surgeons and a significant economic burden for patients and healthcare services worldwide. Bone loss secondary to a local inflammatory response initiated by particulate debris from implants is considered the principal feature of the pathogenesis of osteolysis. In the present study, we analyzed the transcriptional profiling of human macrophages exposed to UHMWPE particles and identified a large number of inflammatory genes that were not identified previously in macrophage responses to wear particles. Our data provide a new insight into the molecular pathogenesis of osteolysis and highlights a number of molecular targets with prognostic and therapeutic implications.

Two-year observation of artificial intervertebral disc replacement: results after supplemental ultra-high strength bioresorbable spinal stabilization.

OBJECT: This 2-year experimental study was conducted to investigate the efficacy of a bioactive three-dimensional (3D) fabric disc for lumbar intervertebral disc replacement. The authors used a bioresorbable spinal fixation rod consisting of a forged composite of particulate unsintered hydroxyapatite/poly-L-lactide acid (HA/PLLA) for stability augmentation. The biomechanical and histological alterations as well as possible device-related loosening were examined at 2 years postoperatively. METHODS: Two lumbar intervertebral discs (L2-3 and L4-5) were replaced with the 3D fabric discs, which were augmented by two titanium screws and a spanning bioresorbable rod (HA/PLLA). The segmental biomechanics and interface bone ingrowth were investigated at 6, 15, and 24 months postoperatively, and results were compared with the other two surgical groups (3D fabric disc alone; 3D fabric disc with additional anterior instrumentation stabilization). The 3D fabric disc and HA/PLLA-spinal segments demonstrated segmental mobility at 15 and 24 months; however, the range of motion (ROM) in flexion-extension decreased to 49 and 40%, respectively, despite statistically equivalent preserved torsional ROM. Histologically there was excellent osseous fusion at the 3D fabric disc surface-vertebral body interface. At 2 years posttreatment, no adverse tissue reaction nor aseptic loosening of the device was observed. CONCLUSIONS: Intervertebral disc replacement with the 3D fabric disc was viable and when used in conjunction with the bioresorbable HA/PLLA spinal augmentation. Further refinements of device design to create a stand-alone type are necessary to obviate the need for additional spinal stabilization.

Comparison of novel ultra-high molecular weight polyethylene tape versus conventional metal wire for sublaminar segmental fixation in the treatment of adolescent idiopathic scoliosis.

STUDY DESIGN: Retrospective study. OBJECTIVES: To compare the surgical outcomes of posterior translational correction and fusion using hybrid instrumentation systems with either sublaminar Nesplon tape or sublaminar metal wire to treat adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Nesplon tape, which consists of a thread of ultra-high molecular weight polyethylene fibers, has advantages over metal wire: (1) its soft and flexible properties avoid neural damage and (2) its flat configuration avoids focal distribution of the stresses to lamina; however, the efficacy of Nesplon tape in the correction of spinal deformity is as yet, still unclear. METHODS: Thirty AIS patients at a single institution underwent posterior correction and fusion using hybrid instrumentation containing hook, pedicle screw, and either sublaminar polyethylene taping (15) or sublaminar metal wiring (15). Patients were evaluated preoperatively, immediately after surgery, and at a 2-year follow-up according to the radiographic changes in curve correction, operating time, intraoperative blood loss, complications, and the Scoliosis Research Society patient questionnaire (SRS-24) score. RESULTS: The average correction rate was 63.0% in the Nesplon tape group and 59.9% in the metal wire group immediately after surgery (P = 0.62). Fusion was obtained in all the patients without significant correction loss in both groups. There was no significant difference in operative time, intraoperative blood loss, and postoperative SRS-24 scores between the 2 groups. Complications were superficial skin infection in a single patient in the Nesplon tape group, and transient sensory disturbance in 1 patient and temporal superior mesenteric artery syndrome in another patient in the metal wire group. CONCLUSIONS: The efficacy of Nesplon tape in correction of deformity is equivalent to that of metal wire, and fusion was completed without significant correction loss. The soft and flexible properties and flat configuration of Nesplon tape make this a safe application for the treatment of AIS with bone fragility or with the fusion areas containing the spinal cord.

An investigational study on the healing process of anterior spinal arthrodesis using a bioactive ceramic spacer and the change in load-sharing of spinal instrumentation.

STUDY DESIGN: Ceramic anterior lumbar interbody arthrodesis was performed using an in vivo sheep model. Observations of fusion status and the load-sharing of spinal instrumentation were studied at sequential intervals for 1 year after surgery. OBJECTIVES: To elucidate the healing process of spinal arthrodesis performed with a bioactive ceramic spacer and the change in load-sharing of anterior spinal instrumentation. SUMMARY OF BACKGROUND DATA: With the improved development of spinal instrumentation, anterior spinal arthrodesis has become a standard spinal reconstruction technique; however, the mechanistic basis underlying the healing process is not well documented. Moreover, it remains unclear how load-distribution through the fusion mass and spinal instrumentation change throughout the healing process. METHODS: Using 24 sheep, a two-level anterior lumbar interbody fusion (L2-L3, L4-L5) was performed using a smooth surface and a porous surface-modified bioactive ceramic, with each segment instrumented using a one-rod anterior spinal instrumentation system. Four animals each were killed at 2, 4, 8, 12, 24, and 52 weeks after surgery. Postmortem analysis included quantification of anterior rod strain under multidirectional flexibility testing and radiographic and histologic analyses of the arthrodesed segments. RESULTS: From 0 to 8 weeks after surgery, the bending strain of the rod gradually decreased despite no obvious bone formation. From 8 to 24 weeks after surgery, the rod strain markedly decreased with the development of bridging trabeculated bone formation between vertebral bodies. After 24 weeks after surgery, minimal changes were observed in rod strain; however, the fusion mass volumetrically increased with corresponding facet joint atrophy. The porous surface-modification of ceramic did not influence the histologic healing process, despite the improvement of interface osseous union rate. CONCLUSIONS: In anterior spinal arthrodesis, spinal instrumentation is mainly exposed to bending stress, with decreased load-sharing with corresponding development of the spinal fusion. Continuous bone remodeling of the anterior fusion mass results in concurrent decreases in spinal instrumentation and posterior spinal element load-transmission. The principal healing mechanism of ceramic anterior interbody spinal fusion is not an osseous union between the ceramic and vertebral body, but bridging bone formation around the ceramic, which directly connects the vertebral bodies above and below the disc.

Bone ingrowth fixation of artificial intervertebral disc consisting of bioceramic-coated three-dimensional fabric.

STUDY DESIGN: The bone-bonding characteristic of the new artificial intervertebral disc consisting of bioceramic-coated three-dimensional fabric was evaluated mechanically and histologically in an in vivo sheep model. OBJECTIVES: To investigate the mechanical properties and the histologic appearance of the interface between the three-dimensional fabric disc and the vertebral body, and to evaluate these alterations in vivo under a spinal segmentally mobile condition. SUMMARY OF BACKGROUND DATA: Bone ingrowth to the bioceramic-coated three-dimensional fabric surface had been demonstrated already under a stable environment in preliminary animal studies. METHODS: For this study, 20 sheep underwent two-level lumbar intervertebral disc replacement with three-dimensional fabric discs (Group I) or bioceramic spacers as a comparative material (Group II). All operative segments were stabilized temporarily with spinal instrumentation for the initial ingrown phase. Four animals each were killed at 4, 6, 15, and 24 months in Group I and at 6 months in Group II, and the operative segments were subjected to either a detachment test or histologic evaluation. RESULTS: The interfacial tensile strength at 6 months was significantly higher in Group I than in Group II. No significant decrease in tensile strength was detected until 24 months after surgery in Group I. Histologically, bone ingrowth to the three-dimensional fabric surface was observed 4 months after surgery, and no aseptic loosening occurred until 24 months after surgery. CONCLUSIONS: The findings show that the three-dimensional fabric disc was firmly fixed to the vertebral body by bone ingrowth, and that this biologic fixation was preserved even under the spinal segmentally mobile condition.