P. D. Sander Dijkstra

Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone

Giant cell tumor (GCT) of bone is a neoplasm of bone characterized by a localized osteolytic lesion. The nature of GCT is an enigma and the cell type(s) and protease(s) responsible for the extensive localized clinicoradiological osteolysis remain unresolved. We evaluated protease expression and cellular distribution of the proteolytic machinery responsible for the osteolysis. mRNA profiles showed that cathepsin K, cathepsin L, and matrix metalloproteinase (MMP)-9 were the preferentially expressed collagenases. Moderate expression was found for MMP-13, MMP-14, and cathepsin S. Specific protease activity assays revealed high cathepsin K activity but showed that MMP-9 was primarily present (98%) as inactive proenzyme. Activities of MMP-13 and MMP-14 were low. Immunohistochemistry revealed a clear spatial distribution: cathepsin K, its associated proton pump V-H(+)-ATPase, and MMP-9 were exclusively expressed in osteoclast-like giant cells, whereas cathepsin L expression was confined to mononuclear cells. To explore a possible role of cathepsin L in osteolysis, GCT-derived, cathepsin L-expressing, mononuclear cells were cultured on dentine disks. No evidence of osteolysis by these cells was found. These results implicate cathepsin K as the principal protease in GCT and suggest that osteoclast-like giant cells are responsible for the osteolysis. Inhibition of cathepsin K or its associated proton-pump may provide new therapeutic opportunities for GCT.

Cement leakage in percutaneous vertebroplasty for osteoporotic vertebral compression fractures: identification of risk factors

BACKGROUND CONTEXT Percutaneous vertebroplasty (PVP) is a common treatment modality for painful osteoporotic vertebral compression fractures (OVCFs). The complication rate of PVP is low, but cement leakage occurs in up to 90% of the treated levels. Recent evidence suggests that sequelae of cement leakage may be more common and clinically relevant than previously thought. Preoperative appreciation of risk factors would therefore be helpful but has not been thoroughly investigated. PURPOSE Identification of preoperative risk factors for the occurrence of cement leakage in PVP for painful OVCFs. STUDY DESIGN Retrospective assessment of risk factors using multivariate analysis. PATIENT SAMPLE Eighty-nine patients treated with PVP for 177 painful OVCFs. OUTCOME MEASURE Occurrence of cement leakage. METHODS The influence of all known risk factors and other parameters potentially affecting the occurrence of cement leakage was retrospectively assessed using multivariate analysis. Patient age, sex, and spinal deformity index; fracture age, level, type, and semiquantitative severity grade (1-4), the presence of an intravertebral cleft and/or cortical disruption on preoperative magnetic resonance imaging (MRI), and the viscosity of bone cement were included. Cement leakage was assessed on direct postoperative computed tomography scanning of the treated levels. In addition to cement leakage in general, three fundamentally different leakage types (cortical, epidural, and anterior venous), with different possible clinical sequelae, were discerned, and their respective risk factors were assessed. RESULTS In 130 of 173 (75.1%) treated OVCFs, cement leakage was detected. Leakage incidence was found to increase approximately linear with advancing severity grade. High fracture semiquantitative severity grade (adjusted per grade relative risk [RR], 1.14; 95% confidence interval [CI], 1.05-1.24; p=.002) and low bone cement viscosity (medium vs. low viscosity: adjusted RR, 0.73; 95% CI, 0.61-0.87; p<.001) were strong risk factors for cement leakage in general. For cortical leakage (in 95% intradiscal leakage), the presence of cortical disruption on MRI (adjusted RR, 1.62; 95% CI, 1.16-2.26; p=.004) and an intravertebral cleft on MRI (adjusted RR, 1.43; 95% CI, 1.07-1.77; p=.017) were identified as additional strong risk factors. CONCLUSIONS High fracture severity grade and low viscosity of polymethylmethacrylate bone cement are general, strong, and independent risk factors for cement leakage. Using MRI assessment, cortical disruption and the presence of an intravertrebral cleft were identified as additional strong risk factors regarding cortical (intradiscal) cement leakage, thereby potentiating anticipation.

The Clinical Approach Toward Giant Cell Tumor of Bone

We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%-27%) or cryosurgery and PMMA (0%-20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra-articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB-derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40-55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable.

New Vertebral Fractures after Percutaneous Vertebroplasty for Painful Osteoporotic Vertebral Compression Fractures: A Clustered Analysis and the Relevance of Intradiskal Cement Leakage

PURPOSE To perform clustered analysis of fracture-free probabilities of intact nontreated vertebrae after percutaneous vertebroplasty (PVP) in painful long-standing osteoporotic vertebral compression fractures (OVCFs) to determine risk factors for new vertebral fractures and estimate fracture-free probabilities of multiple intact nontreated vertebrae given their patient- and vertebra-specific covariate status. MATERIALS AND METHODS Informed consent and institutional review board approval were obtained. A total of 115 patients who underwent PVP for 216 painful long-standing OVCFs were prospectively followed up to detect new OVCFs during the 1st postoperative year. A total of 1031 intact vertebrae were available for clustered analysis of fracture-free probabilities by using a Cox proportional hazard frailty model. A clustered analysis takes clustering or correlation of fracture-free survival probabilities of individual intact vertebrae within one patient into account to improve estimates of fracture-free probabilities and risk factors. Relevant patient- and vertebra-specific covariates were included. Volumetric analysis of intradiskal cement leakage was performed by using a receiver operating characteristic curve (ROC). RESULTS Three- and 12-month vertebral fracture-free probability was 97.0% and 94.5%, respectively. Strong patient-level risk factors included low bone mineral density (hazard ratio [HR], 0.53 per unit increase), high spinal deformity index (HR, 2.23 per five units increase), and low fracture age (HR, 0.52 per 2 months increase). Strong vertebra-specific risk factors were thoracolumbar localization (HR, 2.33), vicinity to the treated level (adjacent level HR, 3.53), and presence of intradiskal cement leakage (HR, 8.21). Fracture-free probabilities of individual vertebrae were clustered within a patient (ie, not independent) (P = .009). The predicted 1-year fracture-free probability of an individual vertebra could be as high as 99.8% or as low as 19.9% based on absence or presence of risk factors, respectively. Larger intradiskal cement leakage volumes were associated with a higher likelihood of occurrence of new adjacent OVCFs (area under the ROC curve, 0.70). CONCLUSION New vertebral fractures after PVP were clustered within patients and depended heavily on the presence or absence of both patient- and vertebra-specific risk factors. Intradiskal cement leakage was a pronounced augmentation-related risk factor, for which a volumetric association was found.

Prediction of torsional failure in 22 cadaver femora with and without simulated subtrochanteric metastatic defects: a CT scan-based finite element analysis.

Background In metastatic bone disease, prophylactic fixation of impending long bone fracture is preferred over surgical treatment of a manifest fracture. There are no reliable guidelines for prediction of pathological fracture risk, however. We aimed to determine whether finite element (FE) models constructed from quantitative CT scans could be used for predicting pathological fracture load and location in a cadaver model of metastatic bone disease. Material and methods Subject-specific FE models were constructed from quantitative CT scans of 11 pairs of human femora. To simulate a metastatic defect, a transcortical hole was made in the subtrochanteric region in one femur of each pair. All femora were experimentally loaded in torsion until fracture. FE simulations of the experimental set-up were performed and torsional stiffness and strain energy density (SED) distribution were determined. Results In 15 of the 22 cases, locations of maximal SED fitted with the actual fracture locations. The calculated torsional stiffness of the entire femur combined with a criterion based on the local SED distribution in the FE model predicted 82% of the variance of the experimental torsional failure load. Interpretation In the future, CT scan-based FE analysis may provide a useful tool for identification of impending pathological fractures requiring prophylactic stabilization.

Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone

BackgroundChondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce.MethodsWe developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential.ResultsWe show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5–8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type.ConclusionsBased on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies.

Long-term clinical outcome of patients with soft tissue sarcomas treated with limb-sparing surgery and postoperative radiotherapy

Abstract Background. To evaluate long-term local control, survival, radiation side effects and functional outcome after limb-sparing surgery followed by postoperative radiotherapy (RT) for soft tissue sarcoma (STS). Material and methods. Between 1995 and 2010, 118 patients with STS of an extremity were treated with limb-sparing surgery and postoperative RT. Follow-up was complete for all patients. Acute and late radiation related toxicities were scored using CTCAE v4.0. Results. Median follow-up was 93 months. RT dose was 60 Gy in 92.4% of the patients; 5.1% received 66 Gy; 2.5% 50–56 Gy. Actuarial local recurrence rates at five and 10 years were 9% and 12%. Five- and 10-year overall survival rates were 69% and 51%. Acute radiation toxicities occurred in 91% of the patients; 19% were grade 3, 2% grade 4. Late radiation toxicities were reported in 71% of the patients: 50% grade 1, 18% grade 2, and 3% grade 3. Limb and joint function after treatment were good, 19% having mild limitation of motion, 1.5% moderate, and 2.5% severe limitations. Conclusion. Limb-sparing surgery with 60 Gy postoperative radiotherapy for patients with STS provides excellent local control and high survival rates with acceptable toxicity and functional outcomes.

Liquid nitrogen or phenolization for giant cell tumor of bone?: a comparative cohort study of various standard treatments at two tertiary referral centers

BACKGROUND The rate of recurrence of giant cell tumor of bone is decreased by use of adjuvant treatments such as phenol, liquid nitrogen, or polymethylmethacrylate (PMMA) during curettage. We assessed recurrence and complication rates and functional outcome after curettage with use of phenol and PMMA, liquid nitrogen and PMMA, and liquid nitrogen and bone grafts. METHODS We retrospectively compared the relative effectiveness of treatment of giant cell tumors of bone at two tertiary centers with a regional function from 1990 to 2010. The 132 (of 201) patients who met the inclusion criteria had a mean age of thirty-three years (range, eleven to sixty-nine years). Treatment assignment depended purely on the center, with primary treatment consisting of curettage with use of phenol and PMMA (n = 82) at one center and with use of either liquid nitrogen and PMMA (n = 26) or liquid nitrogen and bone grafts (n = 24) at the other center. Recurrence and complication rates were determined, and functional outcome was assessed on the basis of the Musculoskeletal Tumor Society (MSTS) score. RESULTS The mean duration of follow-up was eight years (range, two to twenty-two years). Recurrence rates were comparable among the groups (28% for phenol and PMMA, 31% for liquid nitrogen and PMMA, and 38% for liquid nitrogen and bone grafts; p = 0.52). Soft-tissue extension increased the recurrence risk (hazard ratio [HR] = 2.1, 95% confidence interval [CI] = 1.1 to 4.0, p = 0.024). The complication rate was 33% after use of liquid nitrogen and bone grafts, 27% after liquid nitrogen and PMMA, and 11% after phenol and PMMA (p = 0.019); complications included osteoarthritis, infection, postoperative fracture, nonunion, transient nerve palsy, and PMMA leakage. The complication risk was increased by the presence of a pathologic fracture (HR = 4.1, 95% CI = 1.7 to 9.5, p = 0.001) and use of liquid nitrogen (HR = 3.9, 95% CI = 1.5 to 10, p = 0.006 for liquid nitrogen and bone grafts; HR = 3.1, 95% CI = 1.1 to 8.6, p = 0.028 for liquid nitrogen and PMMA). The mean MSTS score was 26 (range, 8 to 30) and was comparable among all three groups (p = 0.52). CONCLUSIONS Recurrence rates were comparable for treatment with phenol and PMMA, liquid nitrogen and PMMA, and liquid nitrogen and bone grafts. Complication rates were higher after use of liquid nitrogen. The functional outcome was excellent in all three cohorts.

What Are the Long-term Results of MUTARS® Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia?

Background Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the longterm results of such prostheses in treatment of primary tumors are scarce. Questions/purposes (1) What proportion of patients experience a mechanical complication with the MUTARS 1 modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? Methods Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS 1 knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval [CI], 8.0‐9.7). Mean age at surgery was 36 years (range, 13‐82 years). Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements (78 uncemented [78 of 89 {88%}, 42 of which were HA-coated [42 of 78 {54%}]) and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. The institution of one or more of the authors (MPAB, MAJvdS, PDSD) has received, during the study period, funding from implantcast GmbH, Buxtehude, Germany. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research 1 neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This work was performed at Leiden University Medical Center, Leiden, The Netherlands.

Mid-Term Outcome After Curettage with Polymethylmethacrylate for Giant Cell Tumor Around the Knee: Higher Risk of Radiographic Osteoarthritis?

BACKGROUND It has been suggested that, when a patient has a giant cell tumor, subchondral bone involvement close to articular cartilage and a hyperthermic reaction from polymethylmethacrylate (PMMA) are risk factors for the development of osteoarthritis. We determined the prevalence, risk factors, and clinical relevance of osteoarthritis on radiographs after curettage and application of PMMA for the treatment of giant cell tumors around the knee. METHODS This retrospective single-center study included fifty-three patients with giant cell tumor around the knee treated with curettage and PMMA between 1987 and 2007. The median age at the time of follow-up was forty-two years (range, twenty-three to seventy years). There were twenty-nine women. Radiographic evidence of osteoarthritis was defined, preoperatively and postoperatively, as Kellgren and Lawrence grade 3 or 4 (KL3-4). We studied the influence of age, sex, tumor-cartilage distance, subchondral bone involvement (≤3 mm of residual subchondral bone), subchondral bone-grafting, intra-articular fracture, multiple curettage procedures, and complications on progression to KL3-4. Functional outcomes and quality of life were assessed with the Short Form-36 (SF-36), Musculoskeletal Tumor Society (MSTS) score, and Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS After a median duration of follow-up of eighty-six months (range, sixty to 285 months), six patients (11%) had progression to KL3, two (4%) had progression to KL4, and one had preexistent KL4. No patient underwent total knee replacement. The hazard ratio for KL3-4 was 9.0 (95% confidence interval [CI] = 2.0 to 41; p = 0.004) when >70% of the subchondral bone was affected and 4.2 (95% CI = 0.84 to 21; p = 0.081) when the tumor-cartilage distance was ≤3 mm. Age, sex, subchondral bone-grafting, intra-articular fracture, multiple curettage procedures, and complications did not affect progression to KL3-4. Patients with KL3-4 reported lower scores on the KOOS symptom subscale (58 versus 82; p = 0.01), but their scores on the other KOOS subscales, the MSTS score (21 versus 24), and the SF-36 (76 versus 81) were similar to those for the patients with KL0, 1, or 2 (KL0-2). CONCLUSIONS Seventeen percent of patients with giant cell tumor around the knee had radiographic findings of osteoarthritis after treatment with curettage and PMMA. A large amount of subchondral bone involvement close to articular cartilage increased the risk for osteoarthritis. The function and quality of life of the patients with KL3-4 were comparable with those for the patients with KL0-2, suggesting that radiographic findings of osteoarthritis at the time of intermediate follow-up had a modest clinical impact. Treatment with curettage and PMMA is safe for primary and recurrent giant cell tumors, even large tumors close to the joint. LEVEL OF EVIDENCE Therapeutic level IV. See Instructions for Authors for a complete description of levels of evidence.