Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge.

Alendronate (ALN) and other bisphosphonates have been used successfully in pediatric patients with osteopenia secondary to connective tissue diseases. Loss of growth in height has not been reported, but concerns remain regarding the effect of these potent antiresorptive agents when used in children and adolescents. High-dose methotrexate (MTX) and other chemotherapy drugs have been implicated in osteoporosis and a high fracture incidence in survivors of childhood cancers and are also associated with osteopenia in adult animals. The effect of high dose MTX on bone density during rapid skeletal growth, however, has not been widely studied, nor has the potentially therapeutic effect of bisphosphonates in this setting. We examined the effects of ALN and MTX administration, alone and in combination, on bone density, morphology, mechanical strength, and longitudinal growth in normal growing rats. Sprague-Dawley rats were given ALN once weekly (0.3 mg/kg) from 5 to 11 weeks of age, with and without a course of methotrexate (MTX) given daily in weeks 1 and 3 (0.75 mg/kg/day). Twenty-four animals were randomly divided into four groups: Control (vehicle), ALN alone, ALN + MTX, and MTX alone. After 6 weeks, the femora, tibiae, and lumbar spine were studied by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, mechanical strength testing, microradiography, light microscopy, and by determination of ash weights and bone lengths. ALN treatment increased bone mineral density (BMD) by 23% to 68%. The largest increases in the femur occurred in the distal third where endochondral bone growth was greatest and included large increases in trabecular bone and total cross-sectional area. ALN + MTX produced similar effects to ALN alone. MTX only reduced BMD by 8% in the vertebrae, but not significantly at other sites. MTX also led to femoral length reductions of 2.9%. The small reductions in BMD due to MTX were overwhelmed by the increases due to ALN, whereas the length loss was unaffected. Transverse density banding corresponding to weekly ALN administrations were clearly evident radiographically throughout the growing skeleton, likely due to decreased resorption and possibly increased mineralization in the bands. ALN or ALN + MTX treatment also led to increases in mechanical strength in the femora. Although MTX administration during growth leads to some BMD reduction, ALN given with MTX eliminates this reduction and in fact bone density and strength increase above control levels.

Ewing's sarcoma of bone tumor cells produces MCSF that stimulates monocyte proliferation in a novel mouse model of Ewing's sarcoma of bone.

Ewing's sarcoma of bone is a primary childhood malignancy of bone that is treated with X-radiation therapy in combination with surgical excision and chemotherapy. To better study Ewing's sarcoma of bone we developed a novel model of primary Ewing's sarcoma of bone and then treated animals with X-radiation therapy. We identified that uncontrolled tumor resulted in lytic bone destruction while X-radiation therapy decreased lytic bone destruction and increased limb-length asymmetry, a common, crippling complication of X-radiation therapy. Osteoclasts were indentified adjacent to the tumor, however, we were unable to detect RANK-ligand in the Ewing's tumor cells in vitro, which lead us to investigate alternate mechanisms for osteoclast formation. Ewing's sarcoma tumor cells and archival Ewing's sarcoma of bone tumor biopsy samples were shown to express MCSF, which could promote osteoclast formation. Increased monocyte numbers were detected in peripheral blood and spleen in animals with untreated Ewing's sarcoma tumor while monocyte number in animals treated with x-radiation had normal numbers of monocytes. Our data suggest that our Ewing's sarcoma of bone model will be useful in the study Ewing's sarcoma tumor progression in parallel with the effects of chemotherapy and X-radiation therapy.

Amifostine before fractionated irradiation protects bone growth in rats better than fractionation alone.

The aim of this study was to determine the independent and combined effects of 100 mg/kg and 200 mg/kg doses of the radioprotectant amifostine and radiotherapy dose fractionation in preserving the integrity of or minimizing damage to the physis during high-dose radiation exposure in an animal model. Thirty-six weanling four-week-old male Sprague-Dawley rats were randomized into six study groups of six animals each. The distal femur and proximal tibia in the right leg of each animal was exposed to X-irradiation, with the contralateral left leg serving as the nonirradiated control. Three groups received a single 25 Gy radiotherapy dose: one group alone, a second group preceded by 100 mg/kg amifostine, and a third preceded by 200 mg/kg amifostine. Three groups received a total of 25 Gy in three equal fractions: one group alone, a second group preceded by 100 mg/kg amifostine, and a third preceded by 200 mg/kg amifostine. Fractionation of the 25 Gy radiation dose reduced the mean percent overall limb growth loss to 44.8%, a statistically significant reduction compared to a mean 58.8% reduced growth with the single 25 Gy dose. Addition of amifostine at 100 and 200 mg/kg before each of the three fractions of radiotherapy further decreased the mean percent overall limb growth loss to 35.2% and 28.5%, respectively, both statistically significant reductions beyond that achieved by fractionation alone.

Sparing of radiation-induced damage to the physis: fractionation alone compared to amifostine pretreatment.

PURPOSE: The purpose of this study was to determine the relative benefits of sparing longitudinal bone growth by fractionation alone compared to pretreatment with amifostine, a chemical that provides differential radioprotection of normal tissues. METHODS AND MATERIALS: Twenty-four weanling 4-week-old male Sprague-Dawley rats were randomized into 2 overall treatment groups: fractionation alone (n = 12) and amifostine pretreatment (n = 12). The distal femur and proximal tibia in the right leg of each animal were exposed to a therapeutic X-irradiation dose (17.5 Gy total in 3 or 5 fractions) with the contralateral left leg as control. In 12 of the animals, amifostine (100 mg/kg) was administered intraperitoneally 20 min before radiation exposure. Six weeks later, growth was calculated based upon measurement of the bone lengths. RESULTS: Fractionated radiation resulted in a mean percent overall limb growth loss of 21. 1 +/- 7.0%. The addition of amifostine brought the mean percent overall limb growth loss to 16.3% +/- 4.6%, which showed a strong trend toward significance compared to fractionation alone (p = 0. 061). The addition of radioprotection with amifostine to 5 fractions irradiation significantly reduced the femoral and overall percentage growth arrest and limb length discrepancy compared to 5 fractions alone. CONCLUSIONS: These results support further investigation of amifostine and other radioprotectants in combination with fractionation for use in growing children requiring radiotherapy to the extremity for malignant tumors.

Inheritance of osteosarcoma and Paget's disease of bone: a familial loss of heterozygosity study.

Pagetoid osteosarcoma is a complication of Paget's disease of bone. Sarcomatous transformation is most often seen in severe, long-standing Paget's disease. Familial clustering of Paget's disease has been described with apparent autosomal dominant inheritance with high penetrance by the sixth decade. Although definitive proof of the specific gene involved remains elusive, some researchers have shown loss of heterozygosity in a region of chromosome 18q in a relatively high percentage of studied patients affected with either Paget's disease alone, in Pagetoid osteosarcoma, and in uncomplicated osteosarcoma. Our patient was diagnosed with Pagetoid osteosarcoma and had a first-degree relative with history of the same. We hypothesized that our patient's tumor samples might contain a similar genetic abnormality. Our analysis of several polymorphic markers from the chromosome 18q21-22 region showed loss of maternally inherited alleles throughout the region. This finding is similar to those described previously and provides further evidence of a susceptibility region relating to this disease. This report describes a father and son, their young ages at diagnosis of Pagetoid sarcoma, the identical sites of disease involvement, and a loss of heterozygosity study illustrating the inheritance of the presumed defective gene.

Cytochemical demonstration of neuromelanin in black pigmented adrenal nodules.

Retrospective review of 363 consecutive autopsy reports in which adrenal examination was noted reveal 8 cases of pigmented adrenal nodules. Black pigmented adrenal nodules have been reported infrequently both as incidental autopsy findings and in association with Cushing's syndrome. The nature of the pigment in these lesions has been assumed to be lipofuscin. Gross and histologic study of seven cases and electron microscopic study of two cases suggest the presence of a neuromelanin component in the pigment, a previously unreported finding in the adrenal cortex. Review of the clinical records of the patients suggested no associations with specific underlying disorders. The prevalence the authors report (2.2%) is less than that of a previous prospective study.

Effects of stem length on mechanics of the femoral hip component after cemented revision.

Bone loss in the proximal femur at the time of revision hip arthroplasty for a failed primary cemented femoral component can substantially reduce the stability of the revision stem. Use of an extended-length femoral component has been suggested to aid in achieving long-term fixation; however, the optimal stem length is unknown. A three-dimensional finite element model of a Charnley-type revision femoral component in a sclerotic shell of cortical bone devoid of cancellous bone was developed, and five different stem lengths ranging from 140 to 273 mm were used. The interface between the sclerotic bone and cement mantle consisted of fibrous tissue. Distal to the sclerotic bone, bonding was allowed between the cement and bone. Relative motion between the cement and bone was reduced substantially when the stem extended beyond the original defect. Maximum principal stresses in the proximal cement mantle decreased from 7.7 to 5.5 MPa, but cement stresses near the distal tip increased from 7.9 to 10.7 MPa when the stem just bridged the defect. Further increases in stem length reduced the distal cement stresses. Increases beyond two femoral diameters had a minor effect on changes in relative motion, cement mantle stresses, and stresses across the cement-bone interface. The results suggest that a femoral component that extends beyond the area of cancellous bone defect by two femoral diameters will be most effective in minimizing stresses and motion that could be associated with clinical loosening of the cemented revision. A shorter stem that just bridges the cancellous bone defect left from the primary procedure may not provide adequate distal fixation due to high cement-bone shear stresses.

Sparing radiation-induced damage to the physis by radioprotectant drugs: laboratory analysis in a rat model.

The radioprotectant compound amifostine (S-2[3-aminopropylamino]-ethylphosphorothioic acid), administered prior to radiotherapy, has been demonstrated to provide differential protection of normal cells from the damaging effects of ionizing radiation. The aim of this pilot was to determine if amifostine could preserve the integrity of, or minimize the damage to, the physis during exposure to radiation in an animal model. Thirty weanling Sprague-Dawley rats were randomized into five groups of six animals each. Groups 1 and 2 received a single exposure to radiation consisting of 12.5 and 17.5 Gy, respectively. Groups 3 and 4 received similar exposures of 12.5 and 17.5 Gy, respectively, but with prior administration of amifostine at 100 mg/kg. Group 5 (control) received neither radiation nor amifostine. At 6 weeks, femoral and tibial lengths were measured in treated and untreated hindlimbs and compared with the baseline lengths to calculate growth. Concordant with previous reports in the literature, the radiation doses of 12.5 and 17.5 Gy reduced net femoral growth in length by a mean of 23% (range = 12-33%, SD = 7.41) and 59% (range = 54-64%, SD = 4.45), respectively, in the irradiated limb. Amifostine reduced anticipated growth loss normally resulting from a single 12.5-Gy radiation dose by 48.9% in the femur, 13.1% in the tibia, and 27.6% overall in the total limb (p < or = 0.05). Similarly, anticipated growth loss from a single 17.5-Gy radiation dose was reduced by 30.8% in the femur, 20.3% in the tibia, and 25.7% overall in the total limb (p < or = 0.05). Amifostine administered prior to clinically relevant radiation exposures significantly reduced the amount of anticipated growth arrest in our animal model.

Novel radioprotectant drugs for sparing radiation-induced damage to the physis.

PURPOSE: To determine if pentoxifylline, interleukin 1alpha, selenium and misoprostol can minimize damage to physeal longitudinal growth during single radiation dose exposure in an animal model. MATERIALS AND METHODS: Eighty-seven weanling Sprague-Dawley rats were randomized into 15 drug/dose groups. All groups received a single 17.5-Gy gamma-irradiation exposure to the right knee, the left limb serving as an internal control. Pentoxifylline was injected 30 min before exposure, sodium selenite and interleukin 1alpha 24 h before exposure and misoprostol 2 h before exposure. Positive controls received 17.5 Gy. At 6 weeks, animals were sacrificed, the hind limb lengths were measured and detailed histomorphometric analysis was performed. RESULTS: Statistically significant reductions (p < or = 0.03) in mean limb length discrepancy compared with irradiation alone were seen following administration of pentoxifylline (50 mg kg(-1)), interleukin 1alpha (15 mcg kg(-1)), selenium (5 mg kg(-1)) and misoprostol (20 mg kg(-1)). Histomorphometric endpoints and growth rate remained altered at 6 weeks despite treatment, but length discrepancy reduction was highly correlated with the appearance of regenerative clones. CONCLUSIONS: Each drug reduced the amount of anticipated growth arrest in the animal model and some compared favourably in magnitude with that previously demonstrated for the established radioprotectant drug amifostine. Restoration of growth appears related to appearance of regenerative clones.

Current combined treatment of high-grade osteosarcomas.

The evaluation and treatment of osteosarcoma have evolved considerably over the past 2 decades, with corresponding dramatic improvements in prognosis. In large part, the improved outlook is attributable to intensive multiagent adjuvant chemotherapy, with better imaging modalities and reconstructive techniques also playing an important role. The current standard treatment for nonmetastatic osteosarcoma includes neoadjuvant chemotherapy, limb-sparing "wide" surgical resection, and reconstruction of the defect. Approximately 80% of patients are spared amputation. Limb salvage should be considered when an adequate surgical margin is attainable without significant neurovascular compromise and the surgical reconstruction is likely to provide better function than amputation. Because a good chemotherapeutic response is an important favorable prognosticator, much recent attention has been focused on predicting response preoperatively to allow closer surgical margins. Aggressive surgical treatment of pulmonary metastases has also been of measurable benefit.

En bloc resection of tumors of the distal end of the ulna.

The operative treatment of malignant tumors and aggressive benign tumors involving the distal end of the ulna often necessitates en bloc resection. The oncological and functional results for eight patients in whom a neoplasm involving the distal end of the ulna had been treated with en bloc resection without reconstruction of the osseous defect were reviewed retrospectively at a mean of seventy-nine months (range, twenty-three to 271 months). Four patients had a giant-cell tumor; two, a low-grade osteogenic sarcoma; one, a hemangioendothelioma; and one, a soft-tissue epithelioid sarcoma with osseous involvement. The amount of bone that was removed from the distal end of the ulna ranged from 3.1 to 9.0 centimeters. In the four patients who had a malignant tumor, a minimum of 7.5 centimeters was removed in order to achieve an adequate wide margin proximally. In the patients who had a benign tumor, a maximum of 6.6 centimeters was resected. Extraperiosteal resection was performed in three of the patients who had a malignant tumor and in one of the patients who had an aggressive giant-cell tumor. Subperiosteal resection was performed in the three patients who had a benign tumor and in one patient who had a parosteal osteogenic sarcoma. None of the patients had local or systemic evidence of recurrence of the tumor. The functional result was excellent for six patients and good for two. Grip strength was reduced by a mean of 15 per cent compared with the strength on the contralateral side, and this reduction did not appear to be related directly to the amount of bone that had been resected. The findings of this study support the concept that routine reconstruction of the osseous defect is not necessary after en bloc resection of a neoplasm of the distal end of the ulna.

A biomechanical analysis of prophylactic fixation for pathological fractures of the distal third of the humerus.

Twenty-four matched pairs of fresh-frozen humeri from human cadavera were divided randomly into four groups, in order to determine the most biomechanically desirable construct for the prophylactic fixation of impending fractures of the distal third of the humerus. Group I comprised intact humeri and matched humeri in which a 50 per cent lateral, semicylindrical cortical defect of the distal third had been created, resulting in a reproducible model of an impending fracture due to a lytic defect involving 50 per cent cortical disruption at the distal end of the humeral medullary canal. In Group II, such a lateral defect was created in both the right and the left, matched humeri. Group III was composed of humeri in which the defect had been fixed prophylactically with a single plate and the contralateral humeri, which had been treated with double-plating. Group IV comprised specimens in which the defect had been fixed with double-plating as well as those fixed with Rush rods. The fixation of each specimen in Groups III and IV was supplemented with bone cement. Each specimen was tested in torsion to failure, and the resulting peak torque, torsional stiffness, and total energy absorbed were analyzed for each group. The Group-I specimens that had a defect had a significantly lower (p < 0.05) peak torque, torsional stiffness, and total energy absorbed than the intact specimens; all of the specimens with a defect failed at the defect, and all of the intact specimens failed proximally. In Group II, there was a high side-to-side association with respect to peak torque, torsional stiffness, and total energy absorbed.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis of chondroid lipoma by fine-needle aspiration biopsy.

Chondroid lipoma is a rare, recently described soft tissue tumor that mimics extraskeletal chondrosarcoma and myxoid liposarcoma. Reports regarding its cytologic and radiological features are sparse. In this report, we describe the cytologic features of this unusual tumor, which include mixed mature lipocytes and lipoblast-like cells embedded in chondromyxoid matrix. We also describe the "target sign appearance" of this tumor in magnetic resonance imaging studies, resembling a neurogenic tumor. More importantly, we demonstrate that a definitive diagnosis of this unusual tumor can be made by fine-needle aspiration biopsy. The usefulness of cell block in fine-needle aspiration biopsy diagnosis of soft tissue tumors is emphasized.

Management of metastatic disease to soft tissue.

Metastases to soft tissue are rare clinical problems. Most metastases are caused by carcinomatous deposits in the skeletal muscle, with lung carcinoma being the most common primary cause. Pain is more commonly observed in association with metastatic soft tissue masses than for soft tissue sarcomas. Treatment should be individualized, but for most carcinomas, initial radiotherapy treatment is recommended. Prognosis varies with the underlying disease, but for the typical patient with a metastatic carcinoma, mean survival duration is approximately 6 months.

Surgical treatment for metastatic disease of the pelvis and the proximal end of the femur.

Advances in the treatment of invasive cancers continue to improve the longevity of patients who have these diseases; thus, the care of patients who have bone metastases is an issue of the utmost importance to the orthopaedic surgeon. In terms of maintaining the ability to walk, no site of potential metastatic involvement is more crucial than the proximal end of the femur and the acetabulum. Advances in femoral and acetabular implants, imaging modalities, and operative techniques now allow reconstruction of even the most complex acetabular and proximal femoral defects. However, the orthopaedic surgeon must recognize the need to approach management of these patients from a multidisciplinary perspective. The oncologist, radiotherapist, rehabilitation medicine specialist, radiologist, and pathologist each have a role to play. Only through cooperation among all members of the team will a patient who has metastatic disease or a myeloma be given the best possible care.

Unusual manifestations of proximal tibiofibular joint synovial cysts.

Synovial cysts emanating from the proximal tibiofibular articulation are commonly symptomatic and may progress to compromise peroneal nerve function. They may cause diagnostic confusion when they present as intraosseous masses or as soft tissue masses causing extrinsic bony erosion. Twelve cases treated surgically are reviewed. Electromyography and nerve conduction studies were valuable in localizing the lesions to the knee when no mass was palpable. Of the six cases involving the peroneal nerve, three required loupe or microscopic dissection of the cyst from within the epineurium. Two other cases had bony changes. Magnetic resonance imaging, though not diagnostic, is valuable in planning the dissection.

Arthrodesis following failed total knee arthroplasty: comprehensive review and meta-analysis of recent literature.

With the increasing duration of follow up on total knee arthroplasties, more revision arthroplasties are being performed. When revision is not advisable, a salvage procedure such as arthrodesis or resection arthroplasty is indicated. This article provides a comprehensive review of the literature regarding arthrodesis following failed total knee arthroplasty. In addition, a statistical meta-analysis of five studies using modern arthrodesis techniques is presented. A statistically significant greater fusion rate with intramedullary nail arthrodesis compared to external fixation is documented. Gram negative and mixed infections are found to be significant risk factors for failure of arthrodesis.

Head and neck replacement prostheses in revision hip arthroplasty: experience with a single modern design.

This study reviewed 52 revision hip arthroplasties in which calcar cortical deficiencies were addressed by implantation of a cemented, modern-design head and neck replacement femoral prosthesis. Mean clinical follow-up was 38 months. Radiographic follow-up beyond 22 months was available for 34 patients (mean: 35.8 months). Mean Mayo clinical hip score (maximum: 80) improved from 28.2 preoperatively to 55.2 at last follow-up. No femoral component was revised for aseptic loosening. However, radiographic analysis demonstrated one prosthesis was probably loose and two were possibly loose. A 92.7% Kaplan-Meier 5-year implant survival rate free from radiographic loosening was projected. This type of prosthesis has yielded good clinical results and excellent early survival.