The Journal of Bone & Joint Surgery最新文献

{"title":"Prophylactic Pinning of the Contralateral Hip in Slipped Capital Femoral Epiphysis: Evaluation of Long-Term Outcome for the Contralateral Hip with Use of Decision Analysis","authors":"W. Schultz, J. Weinstein, Stuart L. Weinstein, Stuart L. Weinstein, Brian G. Smith","doi":"10.2106/00004623-200208000-00003","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00003","url":null,"abstract":"Background: The risk of a contralateral slip in patients who are first seen with a unilateral slipped capital femoral epiphysis has been reported to be 2335 times higher than the risk of an initial slip. The overall prevalence of bilaterality varies widely throughout the literature, with some reports indicating rates as high as 80%. This finding has led many authors to recommend prophylactic pinning of the contralateral asymptomatic hip in patients presenting with a unilateral slipped capital femoral epiphysis.Methods: A decision analysis model with probabilities for the occurrence of contralateral slip and for the severity of slip at different intervals of follow-up was used in the present study. These probabilities were compared with those for various outcomes when the contralateral hip is prophylactically pinned. Scores representing long-term outcome, according to the Iowa hip-rating system, were used in the model as a measure of utility. The probabilities of contralateral slip and the rates of slip severity were taken from large retrospective series. All meaningful clinical scenarios with regard to long-term outcome for the hip were considered in the model. Variables of uncertainty were subjected to sensitivity analyses in order to explore the effect on outcome over the range of plausible values for variables of interest.Results: The results showed a benefit in the long-term outcome for patients who had prophylactic pinning of the contralateral hip. The threshold level at which a benefit is obtained with prophylactic pinning is expressed according to the rates of sequential slip, rates of slips overlooked at follow-up, and complications associated with prophylactic pinning of the contralateral hip.Conclusions: The decision model shows that, when pooled data are used to predict probabilities of sequential slip, treatment of the contralateral hip with prophylactic pinning is beneficial to the long-term outcome for that hip. When considering prophylactic pinning of the contralateral hip, the clinician should use sound clinical judgment with respect to the age, sex, and endocrine status of the patient. Long-term follow-up studies are needed to establish the efficacy of prophylactic pinning, but the predictions in the present study, which are based on findings in the literature, support the safety of this procedure.","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"163 1","pages":"1305–1314"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82655312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Flattening and Apparent Fragmentation Following Ischemic Necrosis of the Capital Femoral Epiphysis in a Piglet Model","authors":"H. Kim, Phi-Huynh Su","doi":"10.2106/00004623-200208000-00006","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00006","url":null,"abstract":"Background: The repair response that follows ischemic necrosis of the immature femoral head and the biological processes that are responsible for the development of femoral head deformity and fragmentation have not been clearly defined. A piglet model was used to study the radiographic and histopathologic changes that occur prior to and during the development of femoral head deformity and fragmentation following ischemic necrosis.Methods: Twenty-five male piglets were studied. A nonabsorbable ligature was placed tightly around the femoral neck to disrupt the blood supply to the capital femoral epiphysis. The animals were killed three days to eight weeks following the induction of ischemia. Radiographs of whole and sectioned femoral heads were made, and the radiographic findings were correlated with the histopathologic changes observed in the specimens.Results: Mild femoral head flattening was observed by four weeks after the induction of ischemia, and severe flattening and fragmentation were observed by eight weeks. The predominant repair response observed following revascularization was osteoclastic bone resorption. Prior to the development of flattening, a large area of osteoclastic bone resorption was observed in the central region of the femoral head. Many osteoclasts were present along the revascularization front, which we believe were responsible for active resorption of the necrotic trabecular bone. Appositional new-bone formation, the hallmark of the repair response in adult ischemic necrosis, was not observed in the area of bone resorption. Instead, the areas of resorbed bone were replaced with a fibrovascular tissue that persisted for up to eight weeks. Appositional new-bone formation was observed, but it was limited to small areas in which revascularization was not followed by osteoclastic bone resorption and in which necrotic trabecular bone was still present. The simultaneous presence of the areas of bone resorption and new-bone formation contributed to the fragmented radiographic appearance of the femoral head.Conclusions: The predominant repair response observed in the piglet model of ischemic necrosis was osteoclastic bone resorption. The early bone loss, the lack of new-bone formation, and the persistence of fibrovascular tissue in the areas of bone resorption compromised the structural integrity of the femoral head and produced progressive femoral head flattening over time. The repair response was different from that observed in femoral heads removed from adult patients with ischemic necrosis and from that observed in the adult rabbit model of ischemic necrosis.Clinical Relevance: The piglet model of ischemic necrosis may be useful for the investigation of the biological processes that lead to the development of femoral head deformity following ischemic necrosis of the immature femoral head.","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"2 1","pages":"1329–1334"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78935138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the Functional Improvement After Total Shoulder Arthroplasty for Osteoarthritis","authors":"E. Fehringer, B. Kopjar, R. Boorman, R. Churchill, Kevin L. Smith, Frederick A. Matsen","doi":"10.2106/00004623-200208000-00009","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00009","url":null,"abstract":"Background: Both shoulder surgeons and patients who are considering total shoulder arthroplasty are interested in the anticipated improvement in shoulder comfort and function after the procedure. The purpose of the present study was to characterize shoulder-specific functional gains in relation to preoperative shoulder function and to present this information in a way that can be easily communicated to patients who are considering this surgery.Methods: We analyzed the preoperative and follow-up shoulder function in patients managed with total shoulder arthroplasty for the treatment of primary glenohumeral osteoarthritis. Functional self-assessments were available for 102 (80%) of 128 shoulders after thirty to sixty months of follow-up. Outcome was assessed with respect to the change in the number of shoulder functions that were performable, the change in shoulder function as a percentage of the preoperative functional deficit, and the change in the ability to perform specific shoulder functions.Results: The average number of shoulder functions that were performable improved from four of twelve preoperatively to nine of twelve postoperatively (p < 0.01). Function improved in ninety-six shoulders (94%). The number of functions that were performable at the time of follow-up was positively associated with preoperative shoulder function (p < 0.05): the better the preoperative function, the better the follow-up function. The improvement in function was greatest for shoulders with less preoperative function (p < 0.01). On the average, patients regained approximately two-thirds of the functions that had been absent preoperatively. Significant improvement was noted in eleven of the twelve shoulder functions that were examined (p < 0.01). The chance of regaining a function that had been absent before surgery was 73%, whereas the chance of losing a function that had been present before surgery was 6%. Older men tended to have greater functional improvement than younger men.Conclusion: Total shoulder arthroplasty for the treatment of primary glenohumeral osteoarthritis significantly improves shoulder function. Postoperative function is related to preoperative function. The improvement that was observed in this clinical series can be conveyed to patients most simply by stating that, after surgery, shoulders typically regained approximately two-thirds of the functions that had been absent preoperatively.","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"187 1","pages":"1349–1353"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81063928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lesser-Toe Abnormalities","authors":"M. Coughlin","doi":"10.2106/00004623-200208000-00023","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00023","url":null,"abstract":"Lesser toe abnormalities, which can result in significant pain and discomfort, are caused by several intrinsic or extrinsic factors including inflammatory arthritis, trauma, congenital abnormalities, neuromuscular disorders, or poorly fitting shoe wear. Identification of the etiology of the deformity is necessary to determine whether conservative or surgical treatment is warranted and to possibly halt progression of the deformity.","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"64 1","pages":"1446–1469"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86183887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Complications After One Hundred and Forty-four Consecutive Hip Revisions with Impacted Morselized Allograft Bone and Cement","authors":"E. Ornstein, I. Atroshi, H. Franzén, R. Johnsson, P. Sandquist, M. Sundberg","doi":"10.2106/00004623-200208000-00005","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00005","url":null,"abstract":"Background: The use of impacted morselized allograft bone and cement in hip revision arthroplasty has been popular, but studies that specifically address intraoperative and postoperative complications have been scarce.Methods: All complications that occurred during, and within the first year after, 144 consecutive hip revision arthroplasties (108 stems and 130 sockets) performed with impacted morselized allograft bone and cement were recorded. Clinical and radiographic follow-up evaluation was performed at three months and at one year after surgery for all patients except eight (seven who had died of causes unrelated to the hip surgery and one who had sustained a stroke). Of these eight patients, seven had a six-week and/or three-month follow-up evaluation.Results: Thirty-nine femoral fractures occurred in thirty-seven hips; twenty-nine of the fractures occurred during surgery and ten, within five months after surgery. Of the intraoperative femoral fractures, twelve were proximal, nine were diaphyseal, and eight involved the greater trochanter. Of the postoperative femoral fractures, one was proximal and nine were diaphyseal. Other intraoperative complications were the creation of a femoral cortical window in seven hips and incidental perforation of the femoral cortex in fourteen. Multivariate analysis showed the risk factors for femoral fracture during or after revision to be concomitant disease, greater deficiency of the femoral bone stock, and an intraoperative femoral window or perforation. Other complications included dislocation of the femoral head in nine hips, deep infection in one hip, persistence of preoperative deep infection in one hip, and superficial wound infection requiring wound débridement in two hips.Conclusions: We found the complication rate to be high after hip revision arthroplasty performed with impacted morselized allograft bone and cement. The most serious complication was postoperative diaphyseal femoral fracture.","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"22 1","pages":"1323–1328"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85664790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Estimated Costs of Manuscripts Associated with OREF Funding","authors":"R. Brand, M. Karam, E. K. Chaw, R. Coutts","doi":"10.2106/00004623-200208000-00024","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00024","url":null,"abstract":"Information is expensive. Anyone who has attempted to accrue a substantial amount of new data realizes this, but apparently few have attempted to quantify such costs. Although we used a variety of computerized literature search strategies, it was not possible to identify any estimates of the costs of producing a research manuscript. Therefore, we undertook the following study to ascertain the costs of producing a publication in musculoskeletal research.\u0000\u0000First, we attempted to determine the costs of producing a published manuscript by using PubMed and a variety of literature search strategies. Although we searched through 2287 scientific references, it was not possible to identify a single article in which the costs of producing a research paper had been directly estimated.\u0000\u0000Two hundred and fifty-two recipients (principal investigators) of Research and Career Development Awards between 1985 and 1998 were then identified from Orthopaedic Research and Education Foundation (OREF) Award Summaries. This source provided data on the duration (typically two years) and total amount of the award, in addition to the investigator's name and institution and the title of the award. The type of award (Research or Career Development) and the degree of the principal investigator were identified. The research projects were classified into one of three categories: biological, biomechanical, or clinical. In most cases (88%), there was a final report from which the numbers of abstracts and publications could be ascertained. To ensure comparability of the costs of the papers, the award amounts were adjusted to 2001 dollars with use of the Consumer Price Index.\u0000\u0000Next, PubMed searches were conducted with use of the name of each principal investigator to determine the number of publications prior to the award, the number of publications in the area of the grant within three years after the completion of the grant period, the number …","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"88 1","pages":"1470–1472"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80917480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryopreservation of Osteochondral Allografts: Dimethyl Sulfoxide Promotes Angiogenesis and Immune Tolerance in Mice","authors":"C. Wingenfeld, R. Egli, A. Hempfing, R. Ganz, M. Leunig","doi":"10.2106/00004623-200208000-00018","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00018","url":null,"abstract":"Background: Although transplantation of cryopreserved bone allografts has become a routine procedure in orthopaedic surgery, biological and immunological impairment remains an unsolved problem that causes clinical failures. Experimental and clinical evidence has indicated that bone grafts that are revascularized early remain viable and contribute to union at the recipient site. Unprotected cryopreservation, used in most bone banks to reduce graft antigenicity, is associated with complete loss of graft viability, potentially contributing to graft failure. The differences in the survival of various cell types during cryopreservation with use of dimethyl sulfoxide, particularly the increased sensitivity of leukocytes to fast freezing, has resulted in a new approach to modulate immunogenicity. On the basis of this concept, it was proposed that a reduction in the immune response and enhanced revascularization of osteochondral allografts could be achieved by rapid cryopreservation with dimethyl sulfoxide. To test this hypothesis, angiogenesis and immune tolerance were quantified in a murine model with use of intravital microscopy.Methods: Fresh osteochondral tissue and osteochondral tissue that had been cryopreserved with and without dimethyl sulfoxide was transplanted into dorsal skinfold chambers as isografts and as allografts in presensitized and nonsensitized recipient mice. To quantify angiogenesis, the onset of hemorrhages in the vicinity of the grafts and the revascularization of the grafts were determined by means of intravital fluorescence microscopy. To determine the recipient's intravascular immune response to the grafts, the leukocyte-endothelium interaction was assessed on the twelfth day after transplantation.Results: Nine of nine fresh isografts were revascularized at a mean (and standard deviation) of 57 ± 33 hours, eight of nine isografts that had been cryopreserved with dimethyl sulfoxide were revascularized at 98 ± 50 hours, and zero of nine isografts that had been cryopreserved without dimethyl sulfoxide were revascularized. Seven of seven fresh allografts were revascularized at 53 ± 6 hours, and ten of ten allografts that had been cryopreserved with dimethyl sulfoxide were revascularized at 82 ± 29 hours. However, signs of revascularization faded in four of the seven fresh allografts whereas reperfusion was maintained in the majority (seven) of the ten grafts frozen in the presence of dimethyl sulfoxide. Similar to the findings associated with unprotected frozen isografts, zero of ten unprotected frozen allografts were revascularized. None of the allografts that had been transplanted into presensitized recipients were revascularized, regardless of whether they had been implanted fresh (nine grafts) or had been implanted after protected (eight grafts) or unprotected (nine grafts) freezing. Quantification of the leukocyte-endothelium interaction revealed a reduction in the intravascular immune response to frozen allografts (both prot","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"51 1","pages":"1420–1429"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76931982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Changes in the Forefoot of Individuals with Diabetes and a Prior Plantar Ulcer","authors":"D. Robertson, Michael J. Mueller, Kirk E. Smith, P. Commean, T. Pilgram, J. Johnson","doi":"10.2106/00004623-200208000-00015","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00015","url":null,"abstract":"Background: Plantar ulcers produced by diabetic foot disease are devastating and costly. Better understanding of the ulcer-producing process is important to improve detection of feet that are at risk and to improve intervention. We identified and quantified soft-tissue and osseous structural changes in the forefoot of diabetic patients with a prior plantar ulcer.Methods: Thirty-two individuals with a mean age (and standard deviation) of 57 ± 11 years were studied; sixteen had diabetes (of a mean of 20 ± 11 years' duration), peripheral neuropathy, and a prior plantar ulcer, and sixteen were matched controls. Computed tomography was used to evaluate forefoot structure, including the plantar soft-tissue (muscle) density, soft-tissue thickness beneath the metatarsal heads, metatarsophalangeal joint angle, metatarsal bone density, and metatarsophalangeal joint arthropathy.Results: Plantar soft-tissue (muscle) density was lower in the individuals with diabetes (mean, 1 HU [Hounsfield unit]) than it was in the controls (mean, 18 HU). There was no difference in the soft-tissue thickness beneath the metatarsal heads (mean, 10 mm) between the individuals with diabetes and the controls, but the soft-tissue thickness decreased with age. The individuals with diabetes had greater extension deformity of the first, second, and third metatarsophalangeal joints and greater arthropathy of the second, third, and fourth metatarsophalangeal joints. There were no significant differences in metatarsal bone density between the groups.Conclusions: There were significant differences between the forefeet of individuals with diabetes and a previous plantar ulcer and those of controls: plantar muscle density was decreased, and metatarsophalangeal joint extension and arthropathy were increased. Interestingly, the soft-tissue thickness under the metatarsal heads in the controls was not greater than that in the diabetic patients.Clinical Relevance: This study demonstrated structural differences between the forefeet of patients with diabetes and a previous ulcer and those of normal age-matched controls. The information can serve to guide new interventions to prevent or treat foot ulcerations in this patient population.","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"26 1","pages":"1395–1404"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84465923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Prospective, Randomized Study of Preoperative Autologous Donation for Hip Replacement Surgery","authors":"D. B. Billote, S. Glisson, D. Green, R. Wixson","doi":"10.2106/00004623-200208000-00002","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00002","url":null,"abstract":"Background: Preoperative autologous blood donation is commonly performed to meet potential perioperative transfusion needs and is a common practice prior to total hip arthroplasty. Using standardized transfusion guidelines, we prospectively analyzed the effectiveness of preoperative autologous donation as a method for decreasing allogeneic transfusion among patients undergoing unilateral primary total hip replacement who were eligible to donate autologous blood.Methods: Patients who were scheduled for primary total hip replacement surgery and who had a preoperative baseline hemoglobin level ≥120 g/L were randomized either to donate two units of blood (autologous donors) or not to donate any blood (nondonors). The donors and nondonors were compared with regard to demographic data, blood-loss volumes, hemoglobin measurements, and transfusion rates. Randomization continued until data were obtained from at least forty patients per treatment group.Results: Of the ninety-six patients who completed the study, forty-two were autologous donors and fifty-four were nondonors. There were no significant differences between the donors and nondonors with regard to age, male:female ratio, estimated blood volume, baseline physical condition, or operative blood loss. The hemoglobin values at the time of enrollment (baseline), at the time of hospital discharge, and six weeks postoperatively were not significantly different between the two groups, although values at the time of admission (129 ± 13 g/L versus 138 ± 12 g/L) and in the recovery room (104 ± 12 g/L versus 115 ± 13 g/L) were significantly lower in the autologous donor group (p < 0.05). No patient in either group required an allogeneic transfusion. Twenty-nine (69%) of the forty-two donors received an autologous transfusion. Thirty-four (41%) of eighty-two autologous units were wasted. At a charge of $379 per autologous unit, there was an additional cost of $758 for each patient in the donor group.Conclusions: Preoperative autologous donation provided no benefit for nonanemic patients undergoing primary total hip replacement surgery. Preoperative autologous donation increased the likelihood of autologous transfusion, wastage of predonated units, and costs.","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"5 1","pages":"1299–1304"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80169785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant Adeno-Associated Virus-Mediated Osteoprotegerin Gene Therapy Inhibits Wear Debris-Induced Osteolysis","authors":"Douglas D. Robertson, Michael J. Mueller, Kirk E. Smith, P. Commean, Thomas Pilgram, Jeffrey E. Johnson","doi":"10.2106/00004623-200208000-00016","DOIUrl":"https://doi.org/10.2106/00004623-200208000-00016","url":null,"abstract":"Background: Aseptic loosening of orthopaedic implants secondary to wear debris-induced osteolysis is a serious problem. Osteoprotegerin (OPG) is a natural decoy protein that inhibits osteoclast activation and bone resorption. This study investigated whether gene therapy using a recombinant adeno-associated viral vector that expresses OPG can inhibit wear debris-induced osteolysis.Methods: A recombinant adeno-associated virus (rAAV) vector co-expressing OPG (rAAV-OPG-IRES-EGFP) was generated. A control vector expressing b-galactosidase (rAAV-LacZ) was also prepared. In vitro validation experiments were performed to determine rAAV-OPG-IRES-EGFP transduction efficiency, OPG expression level and function in bone wafer, and osteoclastic activity.The effect of rAAV-OPG-IRES-EGFP in vivo gene therapy on wear debris-induced osteolysis was then evaluated in a mouse calvarial model in which a single intramuscular injection of the vector was administered prior to the introduction of the wear debris. The effects of the rAAV-OPG-IRES-EGFP gene therapy on wear debris-induced osteoclastogenesis and bone resorption were determined by histomorphometry on day 10.Results: In vitro experiments revealed that 100% of human embryonic kidney 293 cells were transduced at a multiplicity of infection of 1000 with both rAAV-OPG-IRES-EGFP and rAAV-LacZ. At a rAAV-OPG-IRES-EGFP multiplicity of infection of 1000, an OPG concentration of 135 ng/mL of culture media was achieved after four days. Using a bone-wafer assay for osteoclast activity, we found that treatment with rAAV-OPG-IRES-EGFP reduced resorption sevenfold compared with parathyroid hormone-stimulated controls and elevenfold compared with rAAV-LacZ controls. Furthermore, a seventeenfold decrease in RANKL and macrophage colony-stimulating factor-induced splenocyte osteoclastogenesis was observed in co-cultures containing rAAV-OPG-IRES-EGFP-infected fibroblasts.In vivo administration of rAAV-OPG-IRES-EGFP resulted in detectable transduction of myocytes at the injection site and a significant increase in expression of serum OPG levels by the second day (p < 0.05). Maximal concentrations were obtained on day 6 and then leveled off throughout the observation period. In contrast, serum OPG could not be detected in the sham-treated, uninfected titanium-stimulated, or rAAV-LacZ-infected mice. In the control mice, titanium implantation resulted in a threefold increase in the mean number of osteoclasts adjacent to the sagittal suture as well as a twofold increase in the mean area of soft tissue in the sagittal suture compared with the sham-treated mice. In contrast, osteoclast numbers remained at basal levels, and the area of soft tissue in the sagittal suture was markedly reduced in titanium-implanted animals that received rAAV-OPG-IRES-EGFP treatment, demonstrating a complete inhibition of osteolysis in response to titanium particles.Conclusions: A single intramuscular injection of the rAAV-OPG-IRES-EGFP vector can efficient","PeriodicalId":22625,"journal":{"name":"The Journal of Bone & Joint Surgery","volume":"4 1","pages":"1405–1412"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79523065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}