Introduction: Below knee amputation is the safest treatment for aggressive benign and malignant bone tumours of the distal tibia yielding good oncological and functional results. However, in selected patients where limb salvage is feasible and amputation unacceptable to the patient, limb salvage using a distal tibial replacement (DTR) can be considered. This study aims to present the oncological and functional results of the use of this treatment method in our unit. Patients & Methods: A retrospective folder review was performed for all 10 patients who received a modular distal tibial replacement between 01/01/2005 and 31/01/2019 for a primary bone tumour either benign aggressive or malignant. Six were female and the mean age was 31 (1275) years. There were five patients with giant cell tumour of bone, four with osteosarcoma and one with a low-grade chondrosarcoma. The patients with osteosarcoma had neo-adjuvant chemotherapy before surgery. Function was assessed by the Musculoskeletal Tumor Society (MSTS) score. Results: There were six females and four males, with a mean age of 31 (12-75) years. Two patients had local recurrence treated with a BKA and one other patient died of metastases three years postoperatively. At a mean follow-up of three years, the remaining eight patients had a mean MSTS score of 83% (67–93%). There were no radiological signs of loosening, and no revision surgeries. Conclusion: Endoprosthetic replacement of the distal tibia for primary bone tumours can be a safe treatment option in very selected cases.

<p>Giant cell tumour of bone (GCT) is an aggressive primary bone tumour with an unclear etiology that presents with significant local osteolysis due in part to the accumulation of multinucleated osteoclast-like giant cells. However, it is the neoplastic spindle-like stromal cells within GCT that largely direct the pathogenesis of the tumour. I hypothesize that parathyroid hormone-related protein (PTHrP) is a key mediator within GCT that promotes the characteristic osteolytic phenotype by stimulating both bone resorption and giant cell formation. The work presented in this thesis collectively demonstrates that the stromal cells express PTHrP and its receptor, the parathyroid hormone type 1 receptor (PTH1R), and that PTHrP acts in an autocrine/paracrine manner within the tumour to stimulate expression of factors that promote bone resorption. Data are presented that demonstrate that PTHrP stimulates stromal cell expression of the receptor activator of nuclear factor-κB ligand (RANKL), a known essential regulator of osteoclastogenesis, which results in increased formation of multinucleated cells from murine monocytes. Moreover, the GCT stromal cells express matrix metalloproteinase (MMP)-1 and MMP-13. These results suggest that the stromal cells may participate directly in bone resorption through the degradation of type I collagen, the promotion of osteoclast activity, or through a combination of these elements. PTHrP also regulates the expression of MMP-13 by the stromal cells. Experiments with CD40 ligand show that local factors present within the tumour can influence PTHrP expression by the stromal cells and potentiate its catabolic effects by stimulation of RANKL and MMP-13 expression. Together, this thesis presents evidence that suggests PTHrP is an important factor in the pathophysiology of GCT by its actions on promoting catabolism within the tumour. The role of PTHrP in normal physiology and the mechanisms of action presented here suggest that research into the effects of PTHrP within GCT may provide invaluable information that enhances our understanding of the biology of this particularly aggressive bone tumour.</p> / Doctor of Philosophy (PhD)