Osteogenic protein-1 overcomes the inhibitory effect of nicotine on posterolateral lumbar fusion.

STUDY DESIGN: An established rabbit posterolateral lumbar fusion model was used to evaluate the ability of osteogenic protein-1 to overcome the inhibitory effect of nicotine. OBJECTIVE: To determine whether osteogenic protein-1 should be considered as a bone graft alternative for the patient who smokes. SUMMARY OF BACKGROUND DATA: Smoking interferes with the success of posterolateral lumbar fusion. This inhibitory effect has been attributed to nicotine and confirmed in a New Zealand white rabbit model. Osteoinductive protein-1 has been shown to induce posterolateral spine fusion reliably in the rabbit model. The effectiveness with which osteogenic protein-1 induces fusion in the presence of nicotine has not been studied previously. METHODS: Single-level posterolateral intertransverse process fusions were performed at L5-L6 in 18 New Zealand white rabbits. Either autograft or osteogenic protein-1 was used as grafting material. Nicotine was administered via subcutaneous mini-osmotic pumps. The animals were killed 5 weeks after surgery, and the resulting fusion masses were studied. RESULTS: Three rabbits (17%) were excluded because of complications. By manual palpation, two of the eight nicotine-exposed autograft rabbits (25%) and all of the nicotine-exposed osteogenic protein-1 rabbits (100%) were found to be fused. These results correlated well with those obtained from biomechanical testing. Histologically, the fusion zones of the nicotine-exposed autograft rabbits were distinctly less mature than the fusion masses of the nicotine-exposed osteogenic protein-1 rabbits. CONCLUSION: Osteoinductive protein-1 was able to overcome the inhibitory effects of nicotine in a rabbit posterolateral spine fusion model, and to induce bony fusion reliably at 5 weeks.

Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions.

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. MATERIALS AND METHODS: One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, 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.

2000 Young Investigator Research Award winner. Evaluation of OP-1 as a graft substitute for intertransverse process lumbar fusion.

STUDY DESIGN: An established rabbit intertransverse process lumbar fusion model was used to evaluate osteogenic protein (OP)-1 as a potential graft substitute. OBJECTIVES: To determine whether OP-1 is effective in producing intertransverse process lumbar fusion in a rabbit model. SUMMARY OF BACKGROUND DATA: Autogenous iliac crest bone is the gold standard in grafting material for inducing intertransverse process fusion. However, bone graft substitutes are being considered as supplementary or alternative means to achieve such fusion with less morbidity. Relatively little research has been undertaken to investigate the efficacy of OP-1 in this role. METHODS: Single-level intertransverse process lumbar fusions were performed at L5-L6 of 31 New Zealand White rabbits. These were divided into three study groups: autograft, carrier alone, and carrier with OP-1. The animals were killed 5 weeks after surgery. Resultant fusion masses were evaluated by manual palpation, radiography, biomechanical multidirectional flexibility testing, and histology. RESULTS: Seven rabbits (23%) were excluded because of complications. Of the remaining 24 rabbits, 5 (63%) of the 8 in the autograft group had fusion detected by manual palpation, none (0%) of the 8 in the carrier-alone group had fusion, and all 8 (100%) in the OP-1 group had fusion. Radiographs were 55% sensitive and 92% specific for determining fusion. Biomechanical testing results correlated well with those of manual palpation. Histologically, autograft specimens were predominantly fibrocartilage, OP-1 specimens were predominantly maturing bone, and carrier-alone specimens did not show significant bone formation. CONCLUSIONS: OP-1 was found to reliably induce solid intertransverse process fusion in a rabbit model at 5 weeks.

Long-term follow-up of patients with osteochondral allografts. A correlation between immunologic responses and clinical outcome.

This article confirms immunologic responses in humans to histocompatibility antigens (Class I and II) presented by frozen osteochondral allografts. These observations include a correlation of immune responses with long-term clinical outcome. As found in animal models, matching of histocompatibility antigens, particularly to Class II, improves clinical and, presumably, biologic success following implantation of massive frozen bone allografts in humans. The presence of sensitization clearly does not preclude a satisfactory outcome, nor have other reconstructive alternatives (e.g., metallic implants) been shown to be superior in their long-term results.

The Nicolas Andry Award-1995. Fracture healing. Radiation induced alterations.

This study investigated the effects of radiation on fractures in a rat femur model. Two different radiation dosage fractionation schemes (1100 rads given in one dose and 2500 rads given in 10 divided doses over 12 days) and three different times of initiation of radiation (1 day before fracture, 3 or 10 days after fracture) were studied. Fractures exposed to these levels of radiation all appeared to heal during the course of this experiment, although with varying degrees of delay, with the exception of those exposed to a single dose of 1100 rads 3 days after fracture. These animals remained at a more immature level of repair histologically compared with the control group, throughout the entire time evaluated. The strength of the final repair remained less than the control for all the groups receiving treatment. These results may offer some explanation for the clinical observations of an increased incidence of delayed union and nonunion of fractures, an increased incidence of fracture and refracture in irradiated bone, and an increased incidence of fracture and nonunion in constructs using radiation in conjunction with allogeneic bone. Furthermore, the observed effects were generally no different in the animals treated with the two clinically relevant dose fractionation schemes chosen for this study.

A curriculum for the ideal orthopaedic residency. Academic Orthopaedic Society.

The Academic Orthopaedic Society met in April 1994 to discuss manpower issues in orthopaedics. The members developed an approach using the Delphi system to define and obtain consensus on the characteristics of the ideal residency. Six categories of educational attributes were included: General; Clinical Management; Skills and Technical Aspects; Rehabilitation; Basic Science and Research; and Educational Environment. The following year a questionnaire was sent to more than 125 programs in an attempt to have residents and staff anonymously self score their residencies according to the standards defined by the Delphi panels. The results obtained from the 745 responders from 73 programs validate effectively the characteristics of the ideal program and also show the variation among the programs.

Immunologic responses in human recipients of osseous and osteochondral allografts.

A multiinstitutional study was carried out to evaluate immunologic responses for human recipients of massive frozen (-80 degrees C) osseous and osteochondral allografts. Allografts were used to reconstruct skeletal defects associated with a variety of traumatic degenerative and neoplastic disorders. Serum samples were obtained before surgery and from 1 month to 4 years after surgery. Sera were tested by microcytotoxicity against T cells from 60 donors for human leukocyte antigen Class I antibodies and against beta 2-microglobulin treated B cells from 40 donors for human leukocyte antigen Class II antibodies. Panels were selected to represent the majority of known human leukocyte antigen specificities. Of the 84 cases evaluated, 62 (74%) received blood transfusions and 28 of 44 (64%) female recipients had been previously pregnant. Sensitization before transplant was shown in 33 of 84 (39%) patients. After grafting, 49 of 84 (58%) recipients showed evidence of sensitization to Class I antigens and 46 of 84 (55%) recipients showed evidence to sensitization to Class II antigens. Overall sensitization was 67%.

The immune response: the efferent arm.

Once naive T cells encounter antigen, they become primed effector cells. The scope of effector functions mediated by these cells defines the efferent arm of the immune response. The change from naive to primed effector cell is known as adaptive immunity and takes 2 forms: cell mediated, in which T cells mediate effector function, and humoral, in which antibodies are the effector molecules. There are 3 types of effector T cells: inflammatory CD4 T cells, which activate macrophages; helper CD4 T cells, which help B lymphocytes produce antibody; and cytotoxic CD8 T cells, which kill their target cells. The interaction of primed effector cells with their targets results in phenotypic changes in the cells and the secretion of cytokines. These cytokines may be secreted by the primed effector T cell, the target cell, or both. Cytokines function in either autocrine (secreted and used by the same cell) or paracrine (secreted by 1 cell and used by a different cell) circuits and have marked regulatory effects on cells in both the immune and skeletal systems. Many of these cytokines, which were once thought to be products exclusively of immune cells, are now known to be produced by cells of the skeletal system. Both the specific and nonspecific components of the immune response have profound effects on remodeling of the musculoskeletal system during normal and pathologic states.

Effects of prefracture irradiation on the biomechanical parameters of fracture healing.

This study examined the effects on the biomechanical parameters of fracture healing of a single dose of 900 rad (the approximate single-dose equivalent of 2,500 rad in 10 divided doses), given 1 day prior to closed fracture of the femur. The femurs were recovered at 2, 3, 4, 8, and 16 weeks after fracture and were mounted and tested to failure in torsion; the results were compared with those in nonirradiated controls from a previously published study. Prefracture irradiation delayed the progressive increase in biomechanical parameters of fracture healing. The delay was statistically significant up to 8 weeks after fracture. At 4 weeks, the normalized torque was 44% that of intact bone in the treated group compared with 75% for the control group. Sixteen weeks after fracture, the biomechanical and histological parameters of fracture healing of the irradiated femurs were no different from those of the nonirradiated controls. Within the treated group, the irradiated fractures remained significantly weaker than their contralateral intact bone at all time intervals, with a torque of only 79% that of intact bone at 16 weeks. Thus, femoral fractures in rats healed (or regained substantial strength) following palliative doses of radiation delivered 1 day prior to injury, but the repair process was delayed compared with that of nonirradiated controls.

Immune responses to osteochondral allografts: nature and significance.

Osteochondral allografts evoke immune responses. The nature of these immune responses and their biologic significance are still only partially understood. It is clear, however, that cell surface antigens of the major histocompatibility complex represented on the cellular elements of bone grafts cause T-cell activation, specifically those of the suppressor/cytotoxic phenotype. In numerous animal models, the most immunogenic bone allografts (mismatched, fresh) have demonstrated the poorest clinical and biologic outcomes, while more closely matched and/or grafts treated to reduce immunogenicity (frozen, freeze-dried) have more successfully incorporated. These observations support the hypothesis that immune responses against bone-graft related antigens have biologic significance and that reducing these responses may improve clinical results.

Bone graft and total hip arthroplasty. A review.

The success of total hip arthroplasty has been well documented. Aseptic loosening remains the major long-term problem that can lead to significant bone loss and structural deficits. Bone graft has been used with increasing frequency to reconstruct these difficult cases. In this review, the authors detail the biology, biomechanics, and banking of bone grafts. A summary of currently available data on the clinical result of autograft and allograft in reconstructive hip surgery is presented.

Postfracture irradiation effects on the biomechanical and histologic parameters of fracture healing.

The effects of single-dose local irradiation on the biomechanical properties of closed femoral fractures were studied in 75 mature Sprague-Dawley rats. Ten days after fracture, the rats were irradiated with 900 rads at 250 kV to the entire fractured femur. At 2, 3, 4, 8, and 16 weeks after fracture, both fractured and contralateral intact femurs were recovered and evaluated biomechanically by testing to failure in torsion. Results were compared with those from a similar study involving fractures irradiated 3 days after fracture as well as nonirradiated control fractures. Fracture healing progressed faster when irradiation was delayed 10 days than when delayed 3 days, and control fractures healed more rapidly than after either delay. In the 10-day delay group, fractures showed greater strength than did those in the 3-day delay group at 8 weeks, but the strength of irradiated fractures in both groups was similarly depressed at 16 weeks, with a maximum torque well below that of control fractures. These results suggest that delaying radiation exposure of a fracture may mitigate short-term deleterious effects on fracture repair, but that long-term results may be similar to those associated with expeditious irradiation.

Induction of specific T-cell responsiveness to allogeneic bone.

The capacity of fresh murine allogeneic bone to induce a specific immune response in vitro was studied. T-cells stimulated by allogeneic bone in vitro were collected and were characterized for state of activation, cell-surface phenotype, and antigen specificity. The stimulating antigens were determined by genetic mapping with use of recombinant inbred strains of mice and by blocking of mixed lymphocyte cultures with use of neutralizing antibodies. Purified T-cells were cultured alone or with allogeneic or syngeneic bone. In some experiments, the bone marrow was removed before in vitro culture. Responding cells were recovered after a secondary exposure to the stimulating bone. Primed cells were used immediately or cell-lines were developed. The data demonstrated that (1) allogeneic bone activated T-cells and induced their proliferation; (2) bone-induced proliferation of T-cells was specific for antigens that map to the major histocompatibility complex of the bone donor; (3) within the major histocompatibility complex, the antigens responsible for proliferation of T-cells were apparently class-I and class-II determinants; (4) removal of bone-marrow cells had no effect on the ability of that bone to stimulate alloreactivity; and (5) all of the alloreactive T-cells had the cell-surface phenotype Thy-+ CD8+ CD4-.

The influence of ibuprofen on fracture repair: biomechanical, biochemical, histologic, and histomorphometric parameters in rats.

Ibuprofen is a widely used cyclo-oxygenase inhibitor in clinical practice. It has been demonstrated by others to have an inhibitory effect on fracture repair in animals. In the present study, we were unable to demonstrate any significant alterations in fracture biomechanics as measured by torsion testing and fracture stage in mature Sprague-Dawley rats treated with 30 mg/kg/day oral dose of ibuprofen, starting 3 days following fracture, over a 12-week time interval. Fracture histology and serum osteocalcin levels were no different in treated animals than control animals. Furthermore, histomorphometric parameters of bone remodeling, including bone volume and bone formation rate in the intact tail vertebrae of these animals with unilateral femur fractures, were no different between treated and control animals.

Orthopaedic manifestations of sickle-cell disease.

Sickle-cell disease is a well-recognized clinical entity. The pathophysiology of this hemoglobinopathy has been described in detail by numerous investigators since the first case report appeared in 1910. Orthopaedic manifestations of sickle-cell disease account for much of the morbidity associated with this disorder, including pain, osteonecrosis, arthritis, and sepsis. Effective management of these bone and joint sequelae reflect accurate diagnosis, understanding of this disorder's pathophysiology, and knowledge of available medical and surgical treatment alternatives. In this review, the authors summarize the major orthopaedic manifestations of sickle-cell disease with special emphasis placed upon osteonecrosis and osteomyelitis, since these conditions are the most disabling and serious complications in patients with sickle-cell disease.