Recombinant Human Bone Morphogenic Protein‐2 in Fracture Care Quality of life related to fear of falling and hip fracture in older women: a time trade off study. Healing of fresh tibial fractures with OP-1. A preliminary report. Quality of reporting of noninferiority and equivalence randomized trials. An ongoing research for evaluation of treatment with BMPs or AGFs in long bone non-union: protocol description and preliminary results. Natural History of Posterior Iliac Crest Bone Graft Donation for Spinal Surgery: A Prospective Analysis of Morbidity Osteogenic protein-1 for long bone nonunion: an evidence-based analysis. Nonreamed Nailing of Tibial Diaphyseal Fractures in Blunt Polytrauma Patients Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis Recombinant Human Bone Morphogenetic Protein-2 for Treatment of Open Tibial Fractures: A Prospective, Controlled, Randomized Study of Four Hundred and Fifty Patients Health economics: a cost analysis of treatment of persistent fracture non-unions using bone morphogenetic protein-7. Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. The Treatment of Open Tibial Shaft Fractures Using an Interlocked Intramedullary Nail Without Reaming Osteogenic protein-1 in treatment of tibial nonunions: current status. Iliac Crest Bone Graft Donor Site Pain After Anterior Lumbar Interbody Fusion: A Prospective Patient Satisfaction Outcome Assessment Osteogenic Protein-1 (Bone Morphogenetic Protein-7) in the Treatment of Tibial Nonunions: A Prospective, Randomized Clinical Trial Comparing rhOP-1 with Fresh Bone Autograft* Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial.
Recombinant human bone morphogenic protein-2 ( rhBMP-2 ) is an osteoinductive protein that is now available for the acute treatment of open tibial fracture . Data from pre clinical and clinical trials support its role in fracture care . This article summarizes data from two r and omized controlled clinical trials investigating the safety and efficacy of rhBMP-2 in patients with open tibial shaft fractures and tibial fractures with bone defects . Also included is a summary of an economic analysis that examined the cost impact of rhBMP-2  from a hospital and payor perspective OBJECTIVE To estimate the utility ( preference for health ) associated with hip fracture and fear of falling among older women . DESIGN Quality of life survey with the time trade off technique . The technique derives an estimate of preference for health states by finding the point at which respondents show no preference between a longer but lower quality of life and a shorter time in full health . SETTING A r and omised trial of external hip protectors for older women at risk of hip fracture . PARTICIPANTS 194 women aged > /= 75 years enrolled in the r and omised controlled trial or who were eligible for the trial but refused completed a quality of life interview face to face . OUTCOME MEASURES Respondents were asked to rate their own health by using the Euroqol instrument and then rate three health states ( fear of falling , a " good " hip fracture , and a " bad " hip fracture ) by using time trade off technique . RESULTS On an interval scale between 0 ( death ) and 1 ( full health ) , a " bad " hip fracture ( which results in admission to a nursing home ) was valued at 0.05 ; a " good " hip fracture ( maintaining independent living in the community ) 0.31 , and fear of falling 0.67 . Of women surveyed , 80 % would rather be dead ( utility=0 ) than experience the loss of independence and quality of life that results from a bad hip fracture and subsequent admission to a nursing home . The differences in mean utility weights between the trial groups and the refusers were not significant . A test-retest study on 36 women found that the results were reliable with correlation coefficients within classes ranging from 0.61 to 0.88 . CONCLUSIONS Among older women who have exceeded average life expectancy , quality of life is profoundly threatened by falls and hip fractures . Older women place a very high marginal value on their health . Any loss of ability to live independently in the community has a considerable detrimental effect on their quality of life Osteogenic proteins ( OP ) are elements of a class of natural growth factors called Bone Morphogenetic Proteins ( BMP ) . A specific member of this class is OP-1 , a human recombinant protein that has osteogenic properties . The osteoinductive and osteoconductive properties of OP-1 , with its specific collagen matrix , promote the generation of new functionally active , biologically and biomechanically mature bone . We carried out a clinical study to verify the potential of this protein in fresh tibial closed fractures , using OP-1 associated with osteo synthesis by means of a monolateral external fixator CONTEXT Noninferiority and equivalence trials aim to show that the experimental treatment is not clinical ly worse than ( noninferior ) or clinical ly similar to ( equivalent ) a control active treatment . These study objectives imply particular planning and analysis . OBJECTIVE To assess the method ologic quality of reports of r and omized controlled trials of noninferiority and equivalence . DESIGN We search ed MEDLINE and the Cochrane Central Register of Controlled Trials for reports of r and omized controlled trials of noninferiority and equivalence hypotheses published between January 1 , 2003 , and December 31 , 2004 . MAIN OUTCOME MEASURES Data extracted by use of a st and ardized form involved assessment of choice of noninferiority or equivalence margins , sample size calculation , sets of patients analyzed , method of statistical testing and reporting results , and conclusions . RESULTS A total of 162 reports were included in the analysis ( 116 reports of noninferiority and 46 of equivalence ) . The margin defining noninferiority or equivalence was described in most reports ( 156 [ 96.3 % ] ) , with justification of the margin in only 33 ( 20.4 % ) . Almost one quarter of the reports ( 35 [ 21.6 % ] ) did not describe a sample size calculation , and an additional 11 ( 6.8 % ) did not take into account a prespecified noninferiority or equivalence margin . Less than half of the reports ( 69 [ 42.6 % ] ) described both an intent-to-treat ( ITT ; all r and omized patients are included in the analysis ) or modified ITT ( patients who never received treatment are excluded ) and per- protocol ( patients who did not complete the treatment are excluded ) analysis , and only about half of those ( 39 [ 56.5 % ] ) described both types of results . Results were displayed with confidence intervals in 136 reports ( 84.0 % ) . Only 33 articles ( 20.3 % ) fulfilled reporting requirements specific to noninferiority and equivalence trials , 4 of them ( 12.1 % ) with misleading conclusions . CONCLUSIONS Reporting of noninferiority and equivalence trials has important deficiencies : absence of noninferiority or equivalence margin , only an ITT ( or a per- protocol ) analysis performed , and results not adequately reported . Moreover , even for articles fulfilling these requirements , conclusions are sometimes misleading Treatment of long bone non-union ( NU ) continues to be a challenging task for the trauma surgeon often result ing in unsatisfactory results and long-term morbidity . Whilst autologous bone grafting remains the gold st and ard of treatment of these difficult cases , recently , due to the advances made in tissue engineering techniques , other alternatives have become available . In this study we report our preliminary results of treating long bone non-unions using either bone morphogenetic protein-7 ( BMP-7 ) or platelet rich plasma ( PRP ) concentrations .  Twenty-nine cases have entered this study thus far . Preliminary results indicate that  BMP-7 is more efficacious that PRP as there was a significant failure rate of 6.2 % versus 38.5 % between BMP-7 and PRP , respectively Study Design . A prospect i ve study was conducted to examine bone graft donor site morbidity in 106 consecutive patients undergoing posterior spinal fusion . Objectives . To perform a prospect i ve analysis of donor site morbidity , to document the incidence of major complications , and to collect information on the impact of autologous bone graft harvesting from the posterior iliac crest on the overall outcome of spinal surgery . Summary of Background . Bone graft harvesting from the posterior iliac crest for spinal fusion is a source of significant morbidity . Previous retrospective case studies indicate that minor complications are common , but they do not define the natural history and complications of posterior iliac crest bone graft harvesting . Methods . A st and ardized harvesting technique was used . At 3 , 6 , and 12 months after surgery , the patients completed a proforma question naire rating symptoms on a visual analog scale and underwent a postoperative examination by the surgeon . Finally , overall surgical outcome was assessed at 12 months . Results . The major component of morbidity is donor site pain . Mean pain scores were 1.640 at 3 months , 1.812 at 6 months , and 1.207 at 12 months . The pain at 12 months was significantly less than at 3 and 6 months ( P = 0.005 ) , with a trend toward the highest scores at 6 months . A pain score of 0 was reported by 55 % of the patients . Local sensory loss was found in 10 % of the patients . Outcome assessment showed significant differences in morbidity for surgery performed at different spinal levels ( P = 0.001 ) , with lumbosacral surgery result ing in worse outcomes than either cervical ( P < 0.05 ) or thoracolumbar ( P < 0.05 ) surgery . Significantly higher visual analog scores were observed at 6 months in patients with poorer overall outcomes . Conclusions . According to this study , it is reasonable to reassure patients that a good result from spinal surgery will not be compromised by severe symptoms or major morbidity secondary to posterior iliac crest bone graft donation . Before surgery , patients may be advised concerning the risks of donor site pain , which improves significantly by 12 months , local tenderness , and uncommonly localized sensory loss OBJECTIVE To assess the efficacy of osteogenic protein-1 ( OP-1 ) for long bone nonunion . CLINICAL NEED Although most fractures heal within a normal period , about 5 % to 10 % do not heal and are classified as delayed or nonunion fractures . Nonunion and segmental bone loss after fracture , reconstructive surgery , or lesion excision can present complex orthopedic problems , and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life . Many factors contribute to the pathogenesis of a delayed union or nonunion fractures , including deficiencies of calcium , vitamin D , or vitamin C , and side effects of medications such as anticoagulants , steroids , some anti-inflammatory drugs , and radiation . It has been shown that smoking interferes with bone repair in several ways . INCIDENCE OF NONUNION AND DELAYED UNION CASES : An estimated 5 % to 10 % of fractures do not heal properly and go on to delayed union or nonunion . If this overall estimate of incidence were applied to the Ontario population , the estimated number of  delayed union or nonunion in the province would be between 3,863 and 7,725 . TREATMENT OF NONUNION CASES : The treatment of nonunion cases is a challenge to orthopedic surgeons . However , the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site . Fracture stabilization and immobilization is frequently used with the other treatment modalities that provide biological support to the fractured bone . Biological support includes material s that could be served as a source of osteogenic cells ( osteogenesis ) , a stimulator of mesenchymal cells ( osteoinduction ) , or a scaffold-like structure ( osteoconduction ) . The capacity to heal a fracture is a latent potential of the stromal stem cells , which synthesize new bone . This process has been defined as osteogenesis . Activation of the stem cells to initiate osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction . These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process . Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells , the perivascular tissue , and capillaries into these structures . BONE GRAFTS AND BONE GRAFT SUBSTITUTES : Bone graft and bone graft substitutes have one or more of the following components : Undifferentiated stem cellsGrowth factorsStructural latticeUndifferentiated stem cells are unspecialized , multipotential cells that can differentiate into a variety of specialized cells . They can also replicate themselves . The role of stem cells is to maintain and repair the tissue in which they are residing . A single stem cell can generate all cell types of that tissue . Bone marrow is a source of at least 2 kinds of stem cells . Hematopoietic stem cells that form all types of blood cells , and bone marrow stromal stem cells that have osteogenic properties and can generate bone , cartilage , and fibrous tissue . Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures . Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the site of the nonunion fracture . The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow . It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen . Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair . Of the many bone growth factors studied , bone morphogenetics ( BMPs ) have generated the greatest attention because of their osteoinductive potential . The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 ( osteogenic protein ) . Human osteogenic protein-1 ( OP-1 ) has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction . The structural lattice is osteoconductive ; it supports the ingrowth of developing capillaries and perivascular tissues . Three distinct groups of structural lattice have been identified : collagen , calcium sulphate , and calcium phosphate . These material s can be used to replace a lost segment of bone . GRAFTS USED FOR NONUNION : Autologous bone graft is generally considered the gold st and ard and the best material for grafting because it contains several elements that are critical in promoting bone formation , including osteoprogenitor cells , the matrix , and bone morphogenetic proteins . The osteoconductive property of cancellous autograft is related to the porosity of bone . The highly porous , scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone . Sources of cancellous bone are the iliac crest , the distal femur , the greater trochanter , and the proximal tibia . However , harvesting the autologous bone graft is associated with postoperative pain at the donor site , potential injury to the surrounding arteries , nerves , and tissues , and the risk of infection . Thus the development of synthetic material s with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research . Allograft is the graft of tissue between individuals who are of the same species but are of a disparate genotype .  Allograft has osteoconductive and limited osteoinductive properties .  Demineralized bone matrix ( DBM ) is human cortical and cancellous allograft . These products are prepared by acid extraction of allograft bone , result ing in the loss of most of the mineralized component while collagen and noncollagenous proteins , including growth factors , are retained . Figures 1 to 5 demonstrate the osteogenic , osteoinduction , and osteoconduction properties of autologous bone graft , allograft , OP-1 , bone graft substitutes , and bone marrow . Figure 1.Autologous Bone GraftFigure 2.Osteogenic Protein-1Figure 3.Allograft bone and Demineralized Bone MatrixFigure 4.Bone Graft SubstitutesFigure 5.Autologous Bone Marrow Graft NEW TECHNOLOGY BEING REVIEW ED : OSTEOGENIC PROTEIN-1 Health Canada issued a Class IV licence for OP-1 in June 2004 ( licence number 36320 ) . The manufacturer of OP-1 is Stryker Biotech ( Hapkinton , MA ) . The United States Food and Drug Administration ( FDA ) issued a humanitarian device exemption for the application of the OP-1 implant as an " alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed . " Regulatory agencies in Europe , Australia , and New Zeal and have permitted the use of this implant in specific cases , such as in tibial nonunions , or in more general cases , such as in long bone nonunions . According to the manufacturer , OP-1 is indicated for the treatment of long bone nonunions . It is contraindicated in the patient has a hypersensitivity to the active substance or collagen , and it should not be applied at the site of a resected tumour that is at or near the defect or fracture . Finally , it should not be used in patients who are skeletally immature ( < 18 years of age ) , or if there is no radiological evidence of closure of epiphysis . REVIEW STRATEGY OBJECTIVE To summarize the safety profile and effectiveness of OP-1  in the treatment of cases of long bone nonunion and bone defectsTo compare the effectiveness and cost effectiveness of OP-1  in the treatment of long bone nonunions and bone defects with the alternative technologies , particularly the gold st and ard autologous bone graft . LITERATURE SEARCH International Network of Agencies for Health Technology Assessment s ( INAHTA ) , the Cochrane Data base of Systematic Review s and the CCTR ( formerly Cochrane Controlled Trials Register ) were search ed for health technology assessment s. MEDLINE , EMBASE , Medline In Process and Other Non-Indexed Citations were search ed from January 1 , 1996 to January 27 , 2004 for studies on OP-1 . The search was limited to English- language articles and human studies . The search yielded 47 citations . Three studies met inclusion criteria ( 2 RCTs and 1 Ontario-based study presented at an international conference . SUMMARY OF FINDINGS Friedlaender et al. conducted a prospect i ve , r and omized , partially blinded clinical trial on the treatment tibial nonunions with OP-1 . Tibial nonunions were chosen for this study because of their high frequency , challenging treatment requirements , and substantial morbidity . All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months . The patients were r and omized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier . Both groups received reduction and fixation with an intramedullary rod . Table 1 summarizes the clinical outcomes of this study . Table 1 : Outcomes in a R and omized Clinical Trial on Tibial Nonunions : Osteogenic Protein-1 versus Autologous Bone Grafting Clinical Indicator at 9 monthsSuccess by ProcedureOP-1 % (range)Autograft % (range)PWeight-bearing*8685not significantPain on Weight-bearing*8990not significantBridging seen on radiograph ( at least 1 view)7584not significantBridging seen on radiograph ( at least 3 views)6274not significantRepeated surgery*510not significantPhysician satisfaction8690not significantMean operative time in minutes (range)169 ( 58 - 420)178 ( 58 - 420)not significantMean operative blood loss in ml (range)254 (10 - 1,150)345 ( 35 - 1,200).049Mean length of stay in days (range)3.7 ( 0 - 18)4.1 ( 1 - 24)not significantPain at the donor siteN/A80N/AAt 6 months postsurgery20At 12 months postsurgery13Osteomyelitis % (number)3 (2/61)21 ( 13/61 ) . ( ABSTRACT TRUNCATED Summary : The efficacy of nonreamed nailing as the treatment of choice of unstable blunt tibial diaphyseal fractures was studied . From March 1 , 1990 , through August 31 , 1991 , 72 patients with 74 fractures that required fixation were treated . One patient died and six were lost to follow-up , leaving 65 patients with 67 fractures . Follow-up averaged 21 months ( range 5—43 ) . Fisher 's exact and logistic regression analyses were used to compare grade s of open fractures , comminution as classified by Winquist , and dynamic and static nailings . The failure rates of 51 titanium and 16 stainless steel nails  were compared . Times to union were compared by the log rank statistic method . The average time to union was 32 weeks with 26 ( 39 % ) additional operations required to achieve union ; 13 dynamizations ( 12 successful ) , 12 exchange nailings ( 11 successful ) , and one plate and bone graft . The rate of reconstructive procedures to achieve union was a more sensitive indicator of difficulties achieving union than was time to union . Reoperation rates were 33 % for closed or grade I and II fractures compared with 46 % for grade III fractures ( NS ) . Among closed grade I and II static versus dynamic nailing , times to union were 36 versus 25 weeks ( p < 0.01 ) , and the reoperation rates were 44 % versus 13 % ( p < 0.04 ) . Winquist I and II fractures required a 24 % reoperation rate versus 53 % for grade III and IV and segmental fractures ( p<0.01 ) . Static locked fractures required a 48 % reoperation rate versus 12 % for dynamic locked fractures ( p < 0.01 ) . A logistic regression analysis demonstrated that locking mode was the most important factor in determining reoperation rates . Fifteen additional reoperations for infection , broken or painful implants , or to remodel bones that united with an incomplete circumference of cortex were performed . With an additional 12 elective nail removals , the total reoperations numbered 53 ( 79 % ) . Titanium alloy nails had a 2 % failure rate versus 25 % for stainless steel nails ( p < 0.01 ) . Two of 28 ( 7 % ) grade III fractures became infected . All fractures united within 10 ° of normal alignment and 1 cm of length . Nine ( 13 % ) united with an incomplete cortical circumference , refractory to dynamization and full weight bearing . Thirteen of the 58 ( 22 % ) fractures available for an evaluation of ankle motion were symptomatic , with < 10 ° of dorsiflexion . Nonreamed nails are an option in blunt polytrauma patients where immediate stability is critical and in grade III open and other high-energy fractures where secondary operations are acceptable . In other low-energy closed or grade I and II fractures ( especially those statically locked ) , the use of nonreamed nails must be question We r and omly assigned 17 patients with scaphoid non-union at the proximal pole to three treatment groups : ( 1 ) autologous iliac graft ( n=6 ) , ( 2 ) autologous iliac graft + osteogenic protein-1 ( OP-1 ; n=6 ) , and ( 3 ) allogenic iliac graft + OP-1 ( n=5 ) . Radiographic , scintigraphic , and clinical assessment s were performed throughout the follow-up period of 24 months . OP-1 improved the performance of both autologous and allogenic bone implants  and reduced radiographic healing time to 4 weeks compared with 9 weeks in group 1 . Helical CT scans and scintigraphy showed that in OP-1-treated patients sclerotic bone was replaced by well-vascularised bone . The addition of OP-1 to allogenic bone implant equalised the clinical outcome with the autologous graft procedure . Consequently the harvesting of autologous graft can be avoided . RésuméNous avons réparti 17 malades avec une pseudarthrose du pôle proximal du scaphoide en trois groupes aléatoires de traitement : ( 1 ) greffe autologue iliaque ( n=6 ) , ( 2 ) greffe autologue iliaque + protéine osteogenique-1 ( OP-1 ; n=6 ) , et ( 3 ) greffe allogène iliaque + OP-1 ( n=5 ) . L’estimation radiographique , scintigraphique et clinique a été exécutée pendant une période de suivi de 24 mois . L’OP-1 a amélioré la performance des autogreffes et des allogreffes osseuses et a réduit le temps curatif radiographique à 4 semaines , comparé à 9 semaines dans le groupe traité uniquement avec de l’os autologues . Chez les malades traités avec l’OP-1 , la tomodensitométrie hélicoïdale et la scintigraphie ont montré que l’os scléreux était remplacé par de l’os bien vascularisé . L’addition d’OP-1 à la greffe allogène a égalisé le résultat clinique avec la procédure de greffe autologue et a permis de supprimer le temps de prise de greffe Background : The treatment of open fractures of the tibial shaft is often complicated by delayed union and nonunion . The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 ( rhBMP-2 ; dibotermin alfa ) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention . Methods : In a prospect i ve , r and omized , controlled , single-blind study , 450 patients with an open tibial fracture were r and omized to receive either the st and ard of care ( intramedullary nail fixation and routine soft-tissue management [ the control group ] ) , the st and ard of care and an implant containing 0.75 mg/mL of rhBMP-2 ( total dose of 6 mg ) , or the st and ard of care and an implant containing 1.50 mg/mL of rhBMP-2 ( total dose of 12 mg ) . The rhBMP-2 implant ( rhBMP-2 applied to an absorbable collagen sponge ) was placed over the fracture at the time of definitive wound closure . R and omization was stratified by the severity of the open wound . The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively . Results : Four hundred and twenty-one ( 94 % ) of the patients were available for the twelve-month follow-up . The 1.50-mg/mL rhBMP-2 group had a 44 % reduction in the risk of failure ( i.e. , secondary intervention because of delayed union ; relative risk = 0.56 ; 95 % confidence interval = 0.40 to 0.78 ; pairwise p = 0.0005 ) , significantly fewer invasive interventions ( e.g. , bone-grafting and nail exchange ; p = 0.0264 ) , and significantly faster fracture-healing ( p = 0.0022 ) than did the control patients . Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months ( p = 0.0008 ) . Compared with the control patients , those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures ( p = 0.0174 ) , fewer infections ( in association with Gustilo- And erson type-III injuries ; p = 0.0219 ) , and faster wound-healing ( 83 % compared with 65 % had wound-healing at six weeks ; p = 0.0010 ) . Conclusions : The rhBMP-2 implant was safe and , when 1.50 mg/mL was used , significantly superior to the st and ard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures , accelerating fracture and wound-healing , and reducing the infection rate in patients with an open fracture of the tibia OBJECTIVE To compare the cost implication s of treatment of persistent fracture non-unions before and after application of recombinant human bone morphogenetic protein-7 ( BMP-7 ) . METHOD Of 25 fracture non-unions , 9 were treated using BMP-7 alone and 16 using BMP-7 and bone grafting .  These patients were prospect ively followed up , and the costs incurred were analysed . RESULTS The mean number of procedures per fracture performed before application of BMP-7 was 4.16 , versus 1.2 thereafter . Mean hospital stay and cost of treatment per fracture before receiving BMP-7 were 26.84 days and pound 13,844.68 , versus 7.8 days and pound 7338.4 thereafter . The overall cost of treatment of persistent fracture non-unions with BMP-7 was 47.0 % less than that of the numerous previous unsuccessful treatments ( p=0.001 ) . CONCLUSIONS Treating fracture non-unions is costly , but this could be reduced by early BMP-7 administration when a complex or persistent fracture non-union is present or anticipated BACKGROUND The use of recombinant human bone morphogenetic protein-2 ( rhBMP-2 ) to improve the healing of open tibial shaft fractures has been the focus of two prospect i ve clinical studies . The objective of the current study was to perform a subgroup analysis of the combined data from these studies . METHODS Two prospect i ve , r and omized clinical studies were conducted . A total of 510 patients with open tibial fractures were r and omized to receive the control treatment ( intramedullary nail fixation and routine soft-tissue management ) or the control treatment and an absorbable collagen sponge impregnated with one of two concentrations of rhBMP-2 . The rhBMP-2 implant was placed over the fracture at the time of definitive wound closure . For the purpose of this analysis , only the control treatment and the Food and Drug Administration-approved concentration of rhBMP-2 ( 1.50 mg/mL ) were compared . Patients who anticipated receiving planned bone-grafting as part of a staged treatment were excluded from enrollment . RESULTS Fifty-nine trauma centers in twelve countries participated , and patients were followed for twelve months postoperatively . Two subgroups were analyzed : ( 1 ) the 131 patients with a Gustilo- And erson type-IIIA or IIIB open tibial fracture and ( 2 ) the 113 patients treated with reamed intramedullary nailing .  The first subgroup demonstrated significant improvements in the rhBMP-2 group , with fewer bone-grafting procedures ( p = 0.0005 ) , fewer patients requiring invasive secondary interventions ( p = 0.0065 ) , and a lower rate of infection ( p = 0.0234 ) , compared with the control group . The second subgroup analysis of fractures treated with reamed  intramedullary nailing demonstrated no significant difference between the control and the rhBMP-2 groups . CONCLUSIONS The addition of rhBMP-2 to the treatment of type-III open tibial fractures can significantly reduce the frequency of bone-grafting procedures and other secondary interventions . This analysis establishes the clinical efficacy of rhBMP-2 combined with an absorbable collagen sponge implant for the treatment of these severe fractures Summary : Between January 1989 and September 1991 , 117 consecutive open tibial shaft fractures were treated at our institution . Of these , 64 ( 55 % ) met the inclusion criteria and were prospect ively treated according to protocol using unreamed interlocking intramedullary nails as definitive fixation . Wounds were classified according to the method of Gustilo et al. , and included 10 type I , 16 type II , and 38 type III ( 17 type IIIA , 21 type IIIB ) wounds . Contraindications to intramedullary nailing included ( a ) fractures involving the proximal or distal one fifth of the tibia , ( b ) patients with open physes , and ( c ) an associated vascular injury ( type IIIC ) .  Proximal locking was routinely performed , whereas distal locking was used as needed for axial and /or rotational stability . Soft-tissue coverage was obtained after adequate debridement within 7 days : 26 of 64 fractures ( 41 % ) required a soft-tissue procedure ( 17 split-thickness skin grafts , eight free-tissue transfers , one rotational muscle flap ) . Patients were encouraged to bear full weight in a short leg cast or Sarmiento brace as soon as other injuries or pain permitted . Average follow-up time was 24.8 months ( range 12–44 ) and was possible in 46 fractures ( 71.875 % ; nine of 10 type I , 12 of 16 type II , 10 of 17 type IIIA , and 15 of 21 type IIIB ) . Mean time to healing was as follows : type I , 4.8 months ; type II , 4.7 months ; type IIIA , 8.28 months ; and type IIIB , 9.30 months . Twenty fractures exhibited a delay in healing ( > 6 months ) . This included two of 12 type II ( 16 % ) , six of 10 type IIIA ( 60 % ) , and 12 of 15 type IIIB fractures ( 80 % ) . Nine received no treatment , five underwent exchange nailing with a reamed nail , and six were bone grafted . All but one went on to uneventful healing . There were no malunions in either rotation , angulation , or length . Clinical ly , patients complained of only occasional pain . All had full range of motion of the knee and ankle unless associated with other pathology . Complications included one bent nail and 12 broken screws in 10 fractures ( 15 % ) . There were six acute infections ( 13 % ) , all in type III fractures ( one IIIA , five IIIB ) . Two of these patients developed chronic osteomyelitis requiring saucerization ; both had type IIIB fractures . Our data indicate that unreamed tibial nailing is an acceptable technique for use in all open tibial shaft fractures ( excluding type IIIC ) . Our overall chronic infection rate was 4 % , with no chronic infections in types I , II , and IIIA open fractures and a 13 % rate in type IIIB open fractures . In addition , this series was not associated with any malunions . Although delayed union was prevalent , it appeared to be related to the amount of soft-tissue stripping and nail stiffness . The fact that all but one fracture healed with excellent alignment and a minimal infection rate makes this technique suitable for the stabilization of open tibial shaft fractures Between 5 % to 10 % of tibial fractures progress to nonunion , causing substantial disability .  Bone autografts , along with internal fixation , are the usual treatment for these failures , but the morbidity associated with autogenous tissues remains problematic . Bone morphogenetic proteins are currently available for clinical use and pre clinical models , as well as an increasing number of patients treated with these molecules demonstrate their safety and efficacy . Osteogenic Protein-1 , OP-1 , has been evaluated in a r and omized , prospect i ve , multi-institution study of tibial nonunions . Sixty-one patients with 63 nonunions received OP-1 and intramedullary rod fixation , and were compared with 61 patients with 61 nonunions treated with fresh autogenous bone graft and the same fixation . Clinical outcomes ( success in 81 % of OP-1 and 85 % of autograft-treated patients ) and radiographic evaluation ( healing in 75 % of OP-1 and 84 % of autograft-treated patients ) were statistically indistinguishable at 9 months following treatment . No OP-1 or graft-related adverse events occurred . More than 20 % of the autograft group had significant donor-site pain 6 months following surgery . OP-1 is a safe and effective alternative to autogenous bone in treatment of tibial nonunions Background : Autogenous iliac crest bone is the gold-st and ard graft for spinal fusion surgery . Unfortunately , there is a frequent incidence of graft site pain that persists well into the postoperative period with complication rates reported in 2.8 - 39 % of patients . Persistent pain lasting at least 2 years is reported in 15 - 39 % of patients . Objective : The objective of this work was to determine the incidence of acute and persistent pain as well as patient assessment of graft site appearance following iliac crest bone graft harvest for anterior lumbar interbody fusion ( ALIF ) . The control arms of four r and omized prospect i ve multicenter clinical trials evaluating recombinant human bone morphogenetic protein-2 ( rhBMP-2 ) versus autogenous iliac crest bone graft were combined . Two hundred eight patients underwent iliac crest bone graft harvest  for ALIF in threaded cylindrical cages or threaded bone dowels . Patients were assessed at each postoperative visit with question naires evaluating graft site pain intensity , duration , and appearance . Methods : Two hundred eight patients underwent iliac crest bone graft harvest for ALIF as the control group of four r and omized prospect i ve multicenter clinical trials evaluating rhBMP-2 versus autogenous iliac crest bone graft in threaded cylindrical cages or threaded bone dowels . Most patients in the control group had anterior iliac crest graft harvest , equally from the right and left side . Three grafts ( 1.4 % ) were taken from the posterior crest and six ( 2.9 % ) were tricortical . Follow-up was obtained at hospital discharge , 6 weeks , 3 , 6 , 12 , and 24 months . A pain evaluation score was made up of two Visual Analog Scales : one scale measuring intensity , the other frequency of pain . For the intensity scale , a rating of “ 0 ” meant no pain and “ 10 ” was “ as bad as it could be . ” For the frequency scale , a rating of “ 0 ” meant pain was present “ none of the time ” and “ 10 ” meant it was present “ all the time . ” Combining these scales , a total score of 20 indicated the worst pain was present all the time . Patients were also question ed about the graft site appearance . Results : Two hundred eight patients underwent iliac crest harvest , and prospect i ve data were available on 202 patients . At hospital discharge , 2 patients ( 1 % ) had no pain ; this increased to 34 of 199 ( 17 % ) at 6 weeks postoperatively and to 85 of 199 patients ( 43 % ) at 3 months . However , 41 % of patients reported pain at 6 months postoperatively ( 79/192 ) , and 33 % of 168 reported pain at 1 year . One hundred forty-one of 208 patients completed a survey at 24 months , with 31 % reporting some level of pain . At hospital discharge , the graft site pain score ranged from 0 to 20 with a mean of 12.8 , decreasing to 7.3 at 6 weeks , to 3.8 at 3 months , and to 2.9 , 2.4 , and 1.8 at 6 , 12 , and 24 months , respectively . At all time intervals , P values from t tests comparing the mean with 0 were < 0.001 . Graft site appearance at discharge was good in 49 % of patients , fair in 40 % , and poor in 11 % . At 6 weeks , appearance was good in 69 % , fair in 27 % , and poor in 5 % ; at 3 months , it was good in 75 % , fair in 24 % , and poor in 2 % ; at 6 months , it was good in 82 % , fair in 15 % , and poor in 3 % ; at 12 months , it was good in 82 % and fair or poor in 19 % ; and at 24 months , it was good in 84 % and fair or poor in 16 % . There was no significant difference between posterior and anterior harvest sites or bicortical grafts , and all were included in the analysis . Right or left side demonstrated no differences . Discussion : This is the first study known to the authors presenting results of prospect i ve data collected in a multicenter study evaluating iliac crest harvest site pain , both intensity and frequency , as well as graft site appearance . The results demonstrate that 31 % of patients had persistent pain at 24 months postoperatively and 16 % reported fair or poor appearance of their graft site . Conclusions : Persistent donor site pain remains a problem with harvest of autogenous iliac crest bone graft for spinal fusion . This prospect i ve study , the first such study reported for ALIF , confirms that donor site pain remains a significant postoperative management problem Background : The role of bone morphogenetic proteins ( BMPs ) in osseous repair has been demonstrated in numerous animal models . Recombinant human osteogenic protein-1 ( rhOP-1 or BMP-7 ) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions . The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone . Material s and Methods : One hundred and twenty-two patients ( with 124 tibial nonunions ) were enrolled in a controlled , prospect i ve , r and omized , partially blinded , multi-center clinical trial between February , 1992 , and August , 1996 , and were followed at frequent intervals over 24 months . Each patient was treated by insertion of an intramedullary rod , accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft . Assessment criteria included the severity of pain at the fracture site , the ability to walk with full weight-bearing , the need for surgical re-treatment of the nonunion during the course of this study , plain radiographic evaluation of healing , and physician satisfaction with the clinical course . In addition , adverse events were recorded , and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit . Results : At 9 months following the operative procedures ( the primary end-point of this study ) , 81 % of the OP-1-treated nonunions ( n = 63 ) and 85 % of those receiving autogenous bone ( n = 61 ) were judged by clinical criteria to have been treated successfully ( p = 0.524 ) . By radiographic criteria , at this same time point , 75 % of those in the OP-1-treated group and 84 % of the autograft-treated patients had healed fractures ( p = 0.218 ) . These clinical results continued at similar levels of success throughout 2 years of observation , and there was no statistically significant difference in outcome between the two groups of patients at this point ( p = 0.939 ) . All patients experienced adverse events . Forty-four percent of patients in each treatment group had serious events , none of which were related to their bone grafts . More than 20 % of patients treated with autografts had chronic donor site pain following the procedure . Conclusions : rhOP-1 ( BMP-7 ) , implanted with a type I collagen carrier , was a safe and effective treatment for tibial nonunions . This molecule provided clinical and radiographic results comparable with those achieved with bone autograft , without donor site morbidity BACKGROUND Currently , the treatment of diaphyseal tibial fractures associated with substantial bone loss often involves autogenous bone-grafting as part of a staged reconstruction . Although this technique results in high healing rates , the donor-site morbidity and potentially limited supply of suitable autogenous bone in some patients are commonly recognized drawbacks . The purpose of the present study was to investigate the benefit and safety of the osteoinductive protein recombinant human bone morphogenetic protein-2 ( rhBMP-2 ) when implanted on an absorbable collagen sponge in combination with freeze-dried cancellous allograft . METHODS Adult patients with a tibial diaphyseal fracture and a residual cortical defect were r and omly assigned to receive either autogenous bone graft or allograft ( cancellous bone chips ) for staged reconstruction of the tibial defect . Patients in the allograft group also received an onlay application of rhBMP-2 on an absorbable collagen sponge . The clinical evaluation of fracture-healing included an assessment of pain with full weight-bearing and fracture-site tenderness . The Short Musculoskeletal Function Assessment ( SMFA ) was administered before and after treatment . Radiographs were used to document union , the presence of extracortical bridging callus , and incorporation of the bone-graft material . RESULTS Fifteen patients were enrolled in each group . The mean length of the defect was 4 cm ( range , 1 to 7 cm ) . Ten patients in the autograft group and thirteen patients in the rhBMP-2/allograft group had healing without further intervention . The mean estimated blood loss was significantly less in the rhBMP-2/allograft group . Improvement in the SMFA scores was comparable between the groups . No patient in the rhBMP-2/allograft group had development of antibodies to BMP-2 ; one patient had development of transient antibodies to bovine type-I collagen . CONCLUSIONS The present study suggests that rhBMP-2/allograft is safe and as effective as traditional autogenous bone-grafting for the treatment of tibial fractures associated with extensive traumatic diaphyseal bone loss . LEVEL OF EVIDENCE Therapeutic Level II . See Instructions to Authors for a complete description of levels of evidence
BACKGROUND Delay in fracture healing is a complex clinical and economic issue for patients and health services .
OBJECTIVES To assess the incremental effectiveness and costs of bone morphogenetic protein ( BMP ) on fracture healing in acute fractures and nonunions compared with st and ards of care .