Vascular endothelial growth factor pathway promotes osseointegration and CD31hiEMCNhi endothelium expansion in a mouse tibial implant model: an animal study.

AIMS: It is increasingly appreciated that coordinated regulation of angiogenesis and osteogenesis is needed for bone formation. How this regulation is achieved during peri-implant bone healing, such as osseointegration, is largely unclear. This study examined the relationship between angiogenesis and osteogenesis in a unique model of osseointegration of a mouse tibial implant by pharmacologically blocking the vascular endothelial growth factor (VEGF) pathway. MATERIALS AND METHODS: An implant was inserted into the right tibia of 16-week-old female C57BL/6 mice (n = 38). Mice received anti-VEGF receptor-1 (VEGFR-1) antibody (25 mg/kg) and VEGF receptor-2 (VEGFR-2) antibody (25 mg/kg; n = 19) or an isotype control antibody (n = 19). Flow cytometric (n = 4/group) and immunofluorescent (n = 3/group) analyses were performed at two weeks post-implantation to detect the distribution and density of CD31hiEMCNhi endothelium. RNA sequencing analysis was performed using sorted CD31hiEMCNhi endothelial cells (n = 2/group). Osteoblast lineage cells expressing osterix (OSX) and osteopontin (OPN) were also detected with immunofluorescence. Mechanical pull-out testing (n = 12/group) was used at four weeks post-implantation to determine the strength of the bone-implant interface. After pull-out testing, the tissue attached to the implant surface was harvested. Whole mount immunofluorescent staining of OSX and OPN was performed to determine the amount of osteoblast lineage cells. RESULTS: Flow cytometry revealed that anti-VEGFR treatment decreased CD31hiEMCNhi vascular endothelium in the peri-implant bone versus controls at two weeks post-implantation. This was confirmed by the decrease of CD31 and endomucin (EMCN) double-positive cells detected with immunofluorescence. In addition, treated mice had more OPN-positive cells in both peri-implant bone and tissue on the implant surface at two weeks and four weeks, respectively. More OSX-positive cells were present in peri-implant bone at two weeks. More importantly, anti-VEGFR treatment decreased the maximum load of pull-out testing compared with the control. CONCLUSION: VEGF pathway controls the coupling of angiogenesis and osteogenesis in orthopaedic implant osseointegration by affecting the formation of CD31hiEMCNhi endothelium. Cite this article: Bone Joint J 2019;101-B(7 Supple C):108-114.

Clinical and design factors influence the survivorship of custom flange acetabular components.

AIMS: Custom flange acetabular components (CFACs) are a patient-specific option for addressing large acetabular defects at revision total hip arthroplasty (THA), but patient and implant characteristics that affect survivorship remain unknown. This study aimed to identify patient and design factors related to survivorship. PATIENTS AND METHODS: A retrospective review of 91 patients who underwent revision THA using 96 CFACs was undertaken, comparing features between radiologically failed and successful cases. Patient characteristics (demographic, clinical, and radiological) and implant features (design characteristics and intraoperative features) were collected. There were 74 women and 22 men; their mean age was 62 years (31 to 85). The mean follow-up was 24.9 months (sd 27.6; 0 to 116). Two sets of statistical analyses were performed: 1) univariate analyses (Pearson's chi-squared and independent-samples Student's t-tests) for each feature; and 2) bivariable logistic regressions using features identified from a random forest analysis. RESULTS: Radiological failure and revision rates were 23% and 12.5%, respectively. Revisions were undertaken at a mean of 25.1 months (sd 26.4) postoperatively. Patients with radiological failure were younger at the time of the initial procedure, were less likely to have a diagnosis of primary osteoarthritis (OA), were more likely to have had ischial screws in previous surgery, had fewer ischial screw holes in their CFAC design, and had more proximal ischial fixation. Random forest analysis identified the age of the patient and the number of locking and non-locking screws used for inclusion in subsequent bivariable logistic regression, but only age (odds ratio 0.93 per year) was found to be significant. CONCLUSION: We identified both patient and design features predictive of CFAC survivorship. We found a higher rate of failure in younger patients, those whose primary diagnosis was not OA, and those with more proximal ischial fixation or fewer ischial fixation options. Cite this article: Bone Joint J 2019;101-B(6 Supple B):68-76.

Do oxidized zirconium heads decrease tribocorrosion in total hip arthroplasty? A study of retrieved components.

AIMS: The aim of this study was to evaluate fretting and corrosion in retrieved oxidized zirconium (OxZr; OXINIUM, Smith & Nephew, Memphis, Tennessee) femoral heads and compare the results with those from a matched cohort of cobalt-chromium (CoCr) femoral heads. PATIENTS AND METHODS: A total of 28 OxZr femoral heads were retrieved during revision total hip arthroplasty (THA) and matched to 28 retrieved CoCr heads according to patient demographics. The mean age at index was 56 years (46 to 83) in the OxZr group and 70 years (46 to 92) in the CoCr group. Fretting and corrosion scores of the female taper of the heads were measured according to the modified Goldberg scoring method. RESULTS: The OxZr-retrieved femoral heads showed significantly lower mean corrosion scores than the CoCr heads (1.3 (1 to 2.75) vs 2.1 (1 to 4); p < 0.01). Mean fretting scores were also significantly lower in the OxZr cohort when compared with the CoCr cohort (1.3 (1 to 2) vs 1.5 (1 to 2.25); p = 0.02). OxZr heads had more damage in the proximal region compared with the distal region of the head. Location had no impact on damage of CoCr heads. A trend towards increased corrosion in large heads was seen only in the CoCr heads, although this was not statistically significant. CONCLUSION: Retrieval analysis of OxZr femoral heads showed a decreased amount of fretting and corrosion compared with CoCr femoral heads. OxZr seems to be effective at reducing taper damage. Cite this article: Bone Joint J 2019;101-B:386-389.

A rare case of a bisphosphonate-induced peri-prosthetic femoral fracture.

An 81-year-old woman presented with a fracture in the left femur. She had well-fixed bilateral hip replacements and had received long-term bisphosphonate treatment. Prolonged bisphosphonate use has been recently linked with atypical subtrochanteric and diaphyseal femoral fractures. While the current definition of an atypical fracture of the femur excludes peri-prosthetic fractures, this case suggests that they do occur and should be considered in patients with severe osteopenia. Union of the fracture followed cessation of bisphosphonates and treatment with teriparatide. Thus, this case calls into question whether prophylactic intramedullary nailing is sufficient alone to treat early or completed atypical femoral fractures.

A review of the treatment of pelvic discontinuity.

Pelvic discontinuity is a complex entity with a high surgical complication rate and no standardized treatment to date. Revision hip arthroplasty in cases of massive bone loss remains a difficult and unsolved problem. The goal of the surgeon is to preserve limb function by restoring bone stock and the biomechanics of the hip. In cases of severe acetabular bone loss, biologic fixation is often inadequate, requiring extensive bone grafting and reconstructive cages. Reconstructive cages are the most commonly used devices and are designed to bridge bone defects, protect the bone graft, and reestablish the rotation center of the hip. A major limitation of current cages is that they do not allow for biologic fixation. We review the options for treating patients with massive bone loss and pelvic discontinuity and discuss therapeutic options and the clinical and radiological criteria for success.

Fourier transform infrared spectral analysis of degenerative cartilage: an infrared fiber optic probe and imaging study.

A preliminary investigation into the diagnostic potential of an infrared fiber optic probe (IFOP) for evaluating degenerative human articular cartilage is described. Twelve arthritic human tibial plateaus obtained during arthroplasty were analyzed using the IFOP. Infrared spectra were obtained from IFOP contact with articular surface sites visually graded normal or degraded (Collins Scale grade 1 and grade 3, respectively). Comparisons of infrared spectral parameters (peak heights and areas) were made to elucidate spectral indicators of surface degeneration. IFOP spectral analysis revealed subtle but consistent changes between grades 1 and 3 sites. Infrared absorbance bands arising from type II collagen were observed to change with degradation. More degraded tissues exhibited increased amide II (1590-1480 cm(-1))/1338 cm(-1) area ratio (p=0.034) and decreased 1238/1227 cm(-1) peak ratio (p = 0.017); similar changes were seen with Fourier transform infrared imaging spectroscopy (FT-IRIS) analysis. Grades 1 and 3 cartilage showed consistent spectral differences in the amide II, III, and 1338 cm(-1) regions that are likely related to type II collagen degradation that accompanies cartilage degeneration. These results suggest that it may be possible to monitor subtle changes related to early cartilage degeneration, allowing for IFOP use during arthroscopy for in situ determination of cartilage integrity.

An unexpected outcome during testing of commercially available demineralized bone graft materials: how safe are the nonallograft components?

STUDY DESIGN: Radiographic and histologic analyses of commercially available bone graft materials were performed. OBJECTIVE: To compare the osteoinductive efficacy of commercially available demineralized bone matrix material. SUMMARY OF BACKGROUND DATA: The relative in vivo bone formation and toxicology of the nonallograft components the make up various commercially available demineralized bone matrix products are not known. METHODS: An in vivo bone formation model was used in 30 athymic rats. Six different bone grafting materials were tested in subcutaneous and intermuscular locations. After 4 weeks, radiographic and histologic testing of bone formation was performed. RESULTS: Eight of nine rats implanted with Grafton demineralized bone matrix products died 1 to 4 days after implantation of the bone graft material. None of the remaining 10 animals implanted with the four other grafting materials died. The experiment was modified and completed with a lower dose of bone graft material. Pathologic analysis indicated that the cause of death was hemorrhagic necrosis of the kidneys, most likely caused by a toxic effect on the glomeruli and tubules. A possible causative factor may have been the glycerol in the graft material. CONCLUSIONS: Although the volume of Grafton product per kilogram of body weight used in this study was approximately eight times the maximum volume used in humans, the authors believe that this data must be reported because this product is used substantially in clinical settings. In addition, the osteoinductive performance and relative safety of the nonallograft components in all commercially available demineralized bone grafts are not known.

Combination of growth factors inhibits bone ingrowth in the bone harvest chamber.

Previous studies using bone harvest chambers have shown that bone morphogenetic protein-2 inhibits bone ingrowth. The authors hypothesized that the combination of bone morphogenetic protein-2 and a potent angiogenic factor, basic fibroblast growth factor, would result in increased bone formation in this model. Five New Zealand White rabbits were surgically implanted with bone harvest chambers in the proximal metaphyseal region of both tibias. The right leg of each rabbit was implanted with a bovine collagen sponge that was impregnated with recombinant human bone morphogenetic protein-2, basic fibroblast growth factor, or a combination of these factors. The left leg chamber was implanted with the collagen sponge with no growth factors as a control. The bone that grew into the chambers was harvested after 2 weeks, and histomorphologic analysis was performed to determine the amount of tissue and bone ingrowth. The tissue chambers were left empty for 2 weeks between test implants, and this tissue also was harvested, analyzed, and compared with the other samples. The results showed decreased bone formation for the bone morphogenetic protein-2, basic fibroblast growth factor, and combination of bone morphogenetic protein-2 and basic fibroblast growth factor treated groups when compared with the control and empty groups. The combination of bone morphogenetic protein-2 and basic fibroblast growth factor showed inhibition of bone formation that was greater than either growth factor individually. The reason for the inhibition of bone formation with the combination of factors is unknown.

Two-stage exchange hip arthroplasty for deep infection.

Although the risk of infection after total hip arthroplasty has decreased over the last three decades with the use of prophylactic antibiotics, laminar airflow operating rooms and whole-body exhaust suites, deep infection after total hip arthroplasty remains a serious complication. Significant morbidity to the patient and the cost to the health care system remain. During this period of time, diagnostic techniques also have improved including the use of polymerase chain reaction amplification. Treatment options now include: suppressive antibiotics, irrigation and debridement with retention of components, one-stage reimplantation, two-stage reimplantation, and salvage procedures. Based on the medical literature, the successful eradication of a total joint replacement infection with a two-stage reimplantation protocol is over 90% while the success rate with a one-stage protocol is approximately 80%. These success rates may decline however as the prevalence of antibiotic resistant organisms increases. Current controversies regarding two-stage reimplantation protocols include: duration of intravenous antibiotic therapy, timing of the reimplantation, the use of allograft bone in the reconstruction, the choice of fixation (cement versus cementless), and the use of antibiotic-loaded cement spacers.

Bone growth factors.

Osteoblastic culture models, experimental, and clinical models have revealed that bone growth factors influence cellular activity. Growth factors including bone morphogenetic proteins, transforming growth factor beta, platelet-derived growth factor, insulin-like growth factors I and II, and acidic and basic fibroblast growth factors, are powerful tools for fracture healing and bone grafting. Understanding the role that bone growth factors play in bone repair is necessary to apply these factors in a clinical setting.

Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy.

A new class of parathyroid hormone-related protein (PTHrP) analogs has been developed that causes a rapid gain in both trabecular and cortical bone in models of osteopenia. This study investigates the efficacy of the PTHrP analog, RS-66271 ([MAP(1-10)]22-31 hPTHrP(1-34)-NH(2)), as systemic therapy for impaired bone healing in corticosteroid-treated rabbits. A 1 mm defect was created bilaterally in the ulnae of 30 rabbits. Delayed healing was induced by daily injections of prednisone (0.15 mg/kg) beginning 2 months prior to surgery and continuing until killing. Rabbits in the experimental group received daily subcutaneous injections of PTHrP analog RS-66271 (0.01 mg/kg) starting 1 day after surgery. Control animals received subcutaneous normal saline. At the 6 week timepoint, nine of ten ulnae from PTHrP-treated rabbits achieved radiographic union, whereas only two of ten limbs achieved union in control rabbits (p < 0.01). In a separate part of the study, 20 animals (10 control, 10 RS-66271-treated) were killed when radiographic union was achieved bilaterally. In this portion of the study, all limbs in animals treated with PTHrP achieved union by 6 weeks. In the control animals that were allowed to heal for 10 weeks, only 20% of the limbs achieved radiographic union. In addition, ulnae in the PTHrP-analog-treated rabbits showed greater radiographic intensity (20%-40%), larger callus area (209% anteroposterior view, 417% lateral view) (mean area on AP radiographs: control, = 387 +/- 276 mm(2); PTHrP analog, 1195 +/- 408 mm(2)), and greater stiffness (64%) and torque (87%) when compared with controls. RS-66271 was shown to be an effective therapy for preventing impaired bone healing caused by prednisone in a rabbit model.

Biosynthetic bone grafting.

The regeneration of bone remains an elusive yet important goal in the field of orthopaedic surgery. Despite its limitations, autogenous cancellous bone grafting continues to the most effective means by which bone healing is enhanced clinically. Biosynthetic bone grafts currently are being developed as an alternative to autogenous bone grafting. These grafts generally contain one or more of three critical components: (1) osteoprogenitor cells; (2) an osteoconductive matrix; and (3) osteoinductive growth factors. The importance of each of these components based on preclinical data supports their use in biosynthetic bone grafts. The use of growth factors such as bone morphogenetic proteins, transforming growth factor, platelet derived growth factor, and fibroblastic growth factor is reviewed in preclinical long bone defect and spinal fusion models. The use of bone marrow in preclinical and clinical settings is presented with specific emphasis given to the use of bone marrow as a source of osteoprogenitor cells and how the use of these cells can be enhanced with the use of bone morphogenetic protein-2. These data support the concept that although products that contain only one of the three key components of a bone graft may regenerate bone successfully, composites of the three key components will be more successful clinically.

Osteoinductive growth factors in preclinical fracture and long bone defects models.

Fracture healing is a specialized form of the reparative process that the musculoskeletal system undergoes to restore skeletal integrity. This biologic process is a consequence of a complex cascade of biologic events that result in the restoration of bone tissue, allowing for the resumption of musculoskeletal function. Several growth-promoting substances have been identified at the site of skeletal injury and appear to play a physiologic role in fracture healing. This article reviews the effects of these osteoinductive growth factors on bone healing as elucidated by both preclinical in vivo fracture and diaphyseal defect healing models.

The short term outcome of elderly patients with hip fractures.

A prospective outcome study was performed of 100 hip fracture patients at an urban medical center in the United States. After hospitalization 19% were discharged to a rehabilitation facility and 59% were discharged home. At a mean follow-up of 8 months, 81% of patients lived at home, compared to 89% who lived at home prior to the fracture. At follow-up 71% of the patients were able to walk outside with one cane or no aids at all, and 81% were able to perform basic activities of daily living. Half of all patients did not require any home assistance at follow-up. Ten patients had died at follow-up. The goal of operatively treating the patient with a hip fracture is fixation of the fracture with a return to the patient's pre-fracture functional ability. This study illustrates that patients with hip fractures can be effectively treated and discharged home or to a short-term rehabilitation facility with restoration of their pre-fracture functional status.

Enhancement of bone formation in the setting of repeated tissue deformation.

The purpose of this study was to investigate whether the osteoinductive recombinant human bone morphogenetic protein 2, combined with a collagen carrier, could enhance bone formation when exposed to controlled amounts of tissue deformation. Chambers that allow for the multiple harvestings of tissue specimen were used. The devices were implanted in the tibial metaphyses of skeletally mature New Zealand White rabbits. A tissue ingrowth canal in each device either was left empty or filled with a collagen carrier with or without 0.6 microgram of recombinant human bone morphogenetic protein 2. The tissue ingrowth canal was deformed cyclically during a period of 2 minutes daily, according to a previously described deformation protocol. The tissue that developed in the chambers was harvested every 3 weeks. Undecalcified histologic sections of each tissue sample were stained with trichrome and von Kossa stains and subjected to histomorphometric analysis. It was found that deformation decreased the area occupied by bone trabeculae in the empty chambers and carrier controls. The amount of bone formed in the chambers treated with bone morphogenetic protein 2 was significantly greater than that in the chambers subjected to micromotion and left empty or implanted with the collagen carrier. The amount of bone in chambers with motion and bone morphogenetic protein 2 was equal to that in chambers left empty and not subjected to micromotion. Qualitative histologic analysis of the bone formed with bone morphogenetic protein 2 revealed normal bone trabeculae. These findings indicate that bone morphogenetic protein 2 may be useful in augmenting bone formation in conditions that otherwise would favor the formation of fibrous tissue.

Expression of bone morphogenetic proteins in fracture healing.

Fracture healing involves a complex interaction of many local and systemic regulatory factors. Recently, the presence of several bone morphogenetic proteins and their receptors in the fracture healing process has been described. During the early stages of fracture healing, only a minimum number of primitive cells are expressing bone morphogenetic proteins in the fracture callus. As the process of endochondral ossification proceeds, the presence of bone morphogenetic proteins and their receptors increases dramatically, especially in the primitive mesenchymal and chondrocytic cells. While the cartilaginous component of the callus matures with a concomitant decrease in the number of primitive cells, there is a concomitant decrease in presence of bone morphogenetic protein expressing cells. As osteoblasts start to lay down woven bone on the chondroid matrix, these osteoblastic cells express bone morphogenetic proteins and their receptors. The presence of bone morphogenetic proteins decreases, however, as lamellar bone replaces the primitive woven bone. A similar observation is seen in the areas of the callus undergoing intramembranous ossification. Initially, within several days after the fracture, periosteal cells and osteoblasts show intense expression of bone morphogenetic proteins and their receptors. As the woven bone is replaced with mature lamellar bone, the expression of bone morphogenetic protein decreases. These data and the knowledge of bone morphogenetic proteins' strong osteoinductive capacities suggest that individual bone morphogenetic proteins play important yet different roles during fracture repair.

Transforming growth factor beta in fracture repair.

Transforming growth factor betas are a group of polypeptide growth factors that have a wide range of activities in the musculoskeletal and immunological systems. They are thought to play an important role in the development, induction, and repair of bone. This family of closely related genes includes the five known transforming growth factor betas and also the bone morphogenetic proteins. With the development of new techniques to analyze gene expression, the broad range of cellular activities regulated by transforming growth factor beta is beginning to be understood. The critical role that transforming growth factor beta plays in the regulation and stimulation of mesenchymal precursor cells for chondrocytes, osteoblasts, and osteoclasts is now emerging based on a series of in vitro studies. Although transforming growth factor betas appear to stimulate proliferation of precursor cells, it appears that transforming growth factor betas have an inhibitory effect on mature cell lines. In vivo studies indicate the presence of transforming growth factor beta protein and transforming growth factor beta gene expression in normal fracture healing, whereas exogenous transforming growth factor beta administration stimulates the recruitment and proliferation of osteoblasts in fracture healing. Although the cascade of events that leads to bone formation and repair is not completely understood, transforming growth factor beta's central role in the regulation of fracture healing is not disputed.