Steven Gitelis

The use of a surgical grade calcium sulfate as a bone graft substitute: results of a multicenter trial.

In a prospective, nonrandomized, multicenter study, 109 patients with bone defects were treated with a surgical grade calcium sulfate preparation as a bone graft substitute. The calcium sulfate pellets were used in place of morselized cancellous bone graft for the treatment of patients with bone defects who usually would require grafting secondary to trauma, periprosthetic bone loss, tumor, or fusion. The calcium sulfate was used alone or mixed with other materials such as bone marrow aspirate, demineralized bone matrix, or autograft. The defects that were treated were contained and were not necessary for the stability of the bony structure. Radiographic and clinical data were collected at predetermined intervals for 12 months. At 6 months postoperatively, radiographic results for all patients showed that 99% of the calcium sulfate had been resorbed and 88% of the defect was filled with trabeculated bone. There were 13 complications; however, only four (3.6%) were attributable to the product. The results of a subgroup of 46 patients with benign bone lesions treated in the same manner are identical to the results of the overall study population. Surgical grade calcium sulfate pellets are considered a convenient, safe, and readily available bone graft substitute that yield consistent successful results.

Second-generation cementless total hip arthroplasty. Eight to eleven-year results.

Background: Second-generation cementless femoral components were designed to provide more reliable ingrowth and to limit distal osteolysis by incorporating circumferential proximal ingrowth surfaces. We examined the eight to eleven-year results of total hip arthroplasty with a cementless, anatomically designed femoral component and a cementless hemispheric acetabular component. Methods: Ninety-two consecutive primary total hip arthroplasties with implantation of a femoral component with a circumferential proximal porous coating (Anatomic Hip) and a cementless hemispheric porous-coated acetabular component (Harris-Galante II) were performed in eighty-five patients. These patients were prospectively followed clinically and radiographically. Six patients (seven hips) died and five patients (seven hips) were lost to follow-up, leaving seventy-four patients (seventy-eight hips) who had been followed for a mean of ten years (range, eight to eleven years). The mean age at the time of the arthroplasty was fifty-two years. Results: The mean preoperative Harris hip score of 51 points improved to 94 points at the time of final follow-up; 86% of the hips had a good or excellent result. Thigh pain was reported as mild to severe after seven hip arthroplasties. No femoral component was revised for any reason, and none were loose radiographically at the time of the last follow-up. Two hips underwent acetabular revision (one because of dislocation and one because of loosening). Kaplan-Meier survivorship analysis was performed with revision or loosening of any component as the end point. The ten-year survival rate was 96.4% ± 2.1% for the total hip prosthesis, 100% for the femoral component, and 96.4% ± 2.1% for the acetabular component.Radiolucencies adjacent to the nonporous portion of the femoral component were seen in sixty-eight (93%) of the -seventy-three hips with complete radiographic follow-up. Femoral osteolysis proximal to the lesser trochanter was noted in four hips (5%). No osteolysis was identified distal to the lesser trochanter. Periacetabular osteolysis was identified in twelve hips (16%). Five patients underwent exchange of the acetabular liner because of polyethylene wear. Conclusions: This second-generation cementless, anatomically designed femoral component provided excellent clinical and radiographic results with a 100% survival rate at ten years. The circumferential porous coating of this implant improved ingrowth and prevented distal osteolysis at a mean of ten years after the arthroplasty.

Use of a calcium sulfate-based bone graft substitute for benign bone lesions.

Twenty-three patients with a benign bone lesion grafted with calcium sulfate, with and without demineralized bone matrix, were reviewed. At a minimum of 1 year postoperatively, 21 patients had achieved between 76% and 100% bone repair based on anteroposterior and lateral radiographs. Overall, the mean Enneking Functional Evaluation System score was 98%. Calcium sulfate is a well-tolerated, biodegradable, osteoconductive bone graft substitute. It is a reasonable alternative to autogenous bone graft for benign bone lesions.

Radiographic and histologic assessment of calcium sulfate in experimental animal models and clinical use as a resorbable bone-graft substitute, a bone-graft expander, and a method for local antibiotic delivery. One institution's experience.

For more than a decade, the radiographic and histologic appearance of a refined calcium sulfate has been studied in various experimental animal models in our laboratory and in clinical applications. This report summarizes our institution’s experience with calcium sulfate as a synthetic bone graft1, a graft expander (the synergistic combination of calcium sulfate with demineralized bone matrix)2-4, and a method for local delivery of antibiotics5-8. Historically, orthopaedic usage of calcium sulfate was popularized by Peltier. Clinically, we have used calcium sulfate to treat numerous osseous lesions and conditions occurring in the axial and appendicular skeleton, including a variety of benign lesions of bone, osseous defects following implant removal, corrective osteotomy sites, spinal fusion sites, graft sites, fracture defects, and osteomyelitic lesions. Both our research studies and clinical experience have shown consistent osteoconduction, excellent biocompatibility, and complete resorption of calcium sulfate, which was replaced by newly formed bone that ultimately remodeled to be comparable with autogenous bone. The scientific basis for the use of calcium sulfate, the typical radiographic and histologic progression of the implanted material, and the indications and expectations for clinical use are illustrated. Contributions from orthopaedic surgeons from several subspecialties demonstrate the use of calcium sulfate in various applications and anatomic sites. ### Research Synthetic bone-graft materials are of clinical interest because of the morbidity, potential for disease transmission, and procurement issues associated with autografts and allografts. The purpose of this study was to evaluate healing after the use of calcium sulfate as a synthetic bone graft compared with spontaneous healing with no graft material and healing after use of autogenous bone graft in a large medullary defect model1. ### Methods Graft materials: The grafts consisted of either circular 4.7 3-mm tablets of calcium sulfate dihydrate (CaSO4) or autogenous cancellous …

Current trends in the management of adamantinoma of long bones. An international study.

Background: Adamantinoma of long bones is a rare tumor. Published reviews of the orthopaedic management of adamantinoma have involved limited follow-up of small numbers of patients. The oncological aggressiveness of this tumor is unknown. Limb salvage is currently the treatment of choice for most adamantinomas. The purpose of this study was to evaluate the characteristics of adamantinoma of long bones as well as the oncological outcome and the complications of limb salvage operations. Methods: A retrospective study was designed to evaluate the clinical outcomes of limb salvage operations for the treatment of adamantinoma. Data on seventy biopsy-proven cases of adamantinoma treated between 1982 and 1992 at twenty-three different cancer centers in Europe and North America were obtained. Results: The median duration of follow-up was 7.0 years. The male:female ratio was 3:2, and the mean age was thirty-one years. Limb salvage was attempted in 91 percent (sixty-four) of the seventy patients, and the final rate of limb preservation was 84 percent (fifty-nine of seventy). Wide operative margins were obtained in 92 percent (fifty-eight) of sixty-three patients. An intercalary allograft was used to reconstruct the segmental bone defect in 51 percent (thirty-six) of the seventy patients. Reconstruction-related complications occurred in 48 percent (thirty) of sixty-two patients. Nonunion and fracture were the most common complications, occurring in 24 percent (fifteen) and 23 percent (fourteen) of sixty-two patients, respectively. Kaplan-Meier analysis demonstrated a rate of local recurrence of 18.6 percent at ten years. Wide operative margins were associated with a lower rate of local recurrence than marginal or intralesional margins were (p < 0.00005). Kaplan-Meier analysis showed a survival rate of 87.2 percent at ten years. There were no significant relationships between survival and the stage of the tumor (p = 0.058), duration of symptoms (p = 0.90), gender (p = 0.79), or wide operative margins (p = 0.14). Conclusions: Current treatment of adamantinoma, including en bloc tumor resection with wide operative margins and limb salvage, provides lower rates of local recurrence than has been previously reported. In the present study, the limb preservation rate was 84 percent (fifty-nine of seventy), and the survival rate was 87.2 percent at ten years. The rate of complications related to the limb reconstruction was high.

Arthroplasty with a composite of an allograft and a prosthesis for knees with severe deficiency of bone.

We reviewed the clinical and radiographic results of fourteen patients who had a severe deficiency of bone and were managed with a massive allograft in conjunction with a standard total knee prosthesis between 1987 and 1990. The etiology of the bone loss included the failure of a previous total knee prosthesis, a supracondylar fracture of the femur or a fracture of the proximal part of the tibia, and débridement during the first stage of a reconstruction for the treatment of an infection. Thirteen patients had satisfactory clinical and radiographic results after the index procedure. The knee score of The Hospital for Special Surgery improved from an average of 24 points (range, 0 to 54 points) preoperatively to 82 points (range, 37 to 98 points) at the time of the most recent follow-up examination. The average duration of follow-up was forty-three months (range, twenty-nine to sixty-three months). The radiographic and functional results compare favorably with those that have been reported in most studies of otherwise comparable patients who had less deficiency of bone. While considerable risks are associated with the use of allograft bone and the true longevity of reconstructions with such bone is not yet known, the initial and short-term follow-up results support the use of allograft for the restoration of a functional knee joint in a patient who has a severe deficiency of bone.

Increased bone formation using calcium sulfate-calcium phosphate composite graft.

Calcium phosphates (CaPO4) and faster-resorbing calcium sulfate (CaSO4) are successfully employed as synthetic bone grafts for treatment of contained defects. We used a canine critical-sized bone defect model to study an injectable CaSO4/CaPO4 composite graft that incorporated a matrix of CaSO4 and dicalcium phosphate dihydrate into which β-tricalcium phosphate granules were distributed. The area fraction, ultimate compressive stress, and elastic modulus of restored bone and the relative rates of material resorption were compared between the CaSO4/CaPO4 composite graft and pure CaSO4 pellets and to normal canine bone. The area fraction of bone in stained sections and the ultimate compressive stress of the regenerated bone were greater using the CaSO4/CaPO4 composite graft compared to pure CaSO4 pellets after 13 and 26 weeks and were greater than normal bone. The elastic modulus of restored bone in defects treated with CaSO4/CaPO4 composite graft was greater than in defects treated with CaSO4 pellets after 26 weeks, but similar to specimens of normal bone. A small amount of CaSO4/CaPO4 composite graft and no CaSO4 pellets remained after 13 or 26 weeks. This novel CaSO4/CaPO4 composite holds promise for clinical applications where a strong, injectable, slower-resorbing, and biocompatible bone graft substitute would be advantageous.

Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy

Osteosarcoma (OS) is one of the most common malignant bone tumors in early adolescence. Multi-drug chemotherapy has greatly increased the five year survival rate from 20% to 70%. However, the rate has been staggering for 30 years and the prognosis is particularly poor for patients with recurrence and metastasis. Our study aimed to investigate the role of Wnt-β-catenin, Notch and Hedgehog pathway in OS development because all these pathways are involved in skeletal development, tumorigenesis and chemoresistance. Our results showed that the major components in Wnt-β-catenin pathway, e.g. Wnt3a, β-catenin and Lef1, were consistently upregulated in human osteosarcoma cell line Saos2 cells compared to human fetal osteoblasts (hFOB), whereas the changes in the expression levels of Notch and Hh signaling molecules were not consistent. Knocking down β-catenin increased the Saos2 sensitivity to methotrexate (MTX) induced cell death. Consistently, the expression level of β-catenin protein correlated with the invasiveness of OS, as evidenced by more intensive β-catenin immunoreactivity in higher grade OS samples. Chemical inhibition of the Wnt-β-catenin signaling enhanced MTX mediated death of Saos2 cells. A synergistic effect with MTX was observed when both inhibitors for Wnt-β-catenin and Notch pathways were simultaneously used, while the addition of the Hh inhibitor did not further improve the efficacy. Our findings provide some novel insight to OS pathogenesis and lay a foundation for future application of Wnt-β-catenin and Notch inhibitors together with the currently used chemotherapeutic drugs to improve the outcome of OS treatment.

The Use of Large Allografts for Tumor Reconstruction and Salvage of the Failed Total Hip Arthroplasty

Large bone defects have become a more common orthopedic problem in recent year. This is due to the increased enthusiasm for limb salvage surgery as a technique to manage patients with primary bone tumors and for patients who have had multiple joint arthroplasties with subsequent bone loss. One technique that has proven successful for this difficult problem is the use of fresh frozen allografts to reconstruct these skeletal defects. From January 1981 until January 1987, 60 large fragment fresh frozen allografts were used for skeletal reconstruction. These grafts were divided into three basic groups: intercalary, 15; osteoarticular, 16; and allograft-prosthetic composite, 29. The diagnoses included 43 bone tumors, 16 failed total hip arthroplasties, and one traumatic bone loss. The average patient age was 39.7 years and had an average follow-up period of 24 months. The average length of allograft was 12.4 cm. Using the Enneking Functional Evaluation System, the final functional analysis revealed excellent or good results in 86% of the patients and fair or poor results in 14% of the patients. Roentgenological union at the allograft-host bone junction was achieved in 90% of the patients in a mean time of 5.8 months after surgery. An additional three patients obtained union after autogeneic bone grafting. At the time of follow-up evaluation, 92.3% of the patients were free of tumor; they had no local recurrences. The use of fresh frozen allografts represents an acceptable alternative for the reconstruction of large skeletal defects. One can expect good or excellent function for the majority of patients. The best functional results were obtained with the intercalary allografts and the allograft-prosthetic composites.

Local and systemic levels of tobramycin delivered from calcium sulfate bone graft substitute pellets.

We asked if tobramycin-loaded calcium sulfate pellets could be used to maintain high local site antibiotic concentrations for an extended period with minimal systemic levels and without adverse effects on vital organs. Calcium sulfate pellets loaded with 10% tobramycin were implanted in contained medullary defects in the proximal humeri of canines. The number of pellets implanted was calculated to yield an equivalent human maximum prescribed dose, and 1.8-fold this dose. These doses converted to approximately 20 mg/kg, and 36 mg/kg, respectively, for the canine. Local and systemic tobramycin levels, pellet resorption, bone response, clinical pathology parameters, and histopathologic responses of potential target organs were analyzed to determine if there was any adverse response for a 28-day period. Serum tobramycin was elevated for less than one day while local levels remained elevated for at least 14 days, and in some animals, 28 days. Tobramycin delivered locally from calcium sulfate pellets had no apparent adverse effect on clinical pathology parameters or on any of the organs that were analyzed. In addition, bone formation and pellet resorption followed patterns typically seen with calcium sulfate materials.