Earlier osteodensitometric results of femoral periprosthetic bone showed that postoperative antiresorptive treatment with alendronate following total hip arthroplasty (THA) reduces the periprosthetic bone loss that commonly occurs in the first months after surgery. However, whether alendronate can prevent periprosthetic bone loss over the long term, or if bone loss occurs after discontinuing alendronate is unknown. Femoral periprosthetic bone mineral density (BMD) was assessed in 49 patients 6 years after cementless total hip arthroplasty using dual energy X-ray absorptiometry. Twenty-nine patients were treated postoperatively with alendronate and 20 control patients received no treatment. All patients were followed up at 12 months after surgery in a prospective randomized study. The bone mineral density was evaluated in 7 regions of interest according to the Gruen protocol. Six years after total hip arthroplasty, no significant changes were detected in femoral periprosthetic BMD when compared with results at 1 year, and the bone loss in patients with postoperative alendronate treatment was still significantly less than those without treatment. These results suggest that the prevention of femoral periprosthetic bone loss following THA achieved by postoperative antiresorptive treatment with alendronate is of long-standing effect, and further bone loss does not occur after the first postoperative year. ß

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Osteosarcomas (OS) are the most frequent primary malignant bone tumors in humans. Even though OS are chemosensitive, about 30% of patients must be considered poor responders and consequently have a dismal long term prognosis. The Hedgehog (Hh) gene is crucial in the signalling pathways of proliferation and differentiation during embryonic development. There is evidence that uncontrolled activation of this pathway results in specific types of cancer and that inhibition of Hh signalling is able to suppress tumour growth and to induce apoptosis of neoplastic cells. This study investigates the impact of the steroidal alkaloid and Hh-inhibitor cyclopamine on osteosarcoma cells. Thus we demonstrate the drug's impact on cellular proliferation, cell cycle cell death as well as the cells' metabolism. We here demonstrate that cyclopamine exhibits a high efficacy against the osteosarcoma cell lines HOS, SaOS and OS-KA, a self-established primary osteosarcoma cell line. In particular, cyclopamine is able to inhibit proliferation and to promote cell death. Our results provide evidence for the potency of the Hh-inhibitor cyclopamine as a future treatment of osteosarcomas.

Chemoresistant metastases of osteosarcoma in humans limit survival in approximately one third of patients. Furthermore, aggressive chemotherapy can lead to side effects and occurrence of secondary malignancies in long time survivors. Therefore, supplemental medical strategies are worthwhile. The well-directed manipulation of cancer-signaling-cascades is an appealing approach. Targeting of the Hedgehog-pathway in cancer has led to promising results in vitro as well as in vivo in a number of different tumor types. Recently, the impact of cyclopamine, which inhibits Hedgehog signaling by binding to the receptor Smoothened, was shown in different human osteosarcoma cell lines in vitro and in vivo. In the present study we examined the influence of cyclopamine on early pulmonary metastases in vivo. Murine osteosarcoma cells, OS-50, were injected into the lateral tail vein of young BALB/c mice. Treatment with subcutaneous cyclopamine injections began after three days. Two weeks later, the animals were sacrificed and the number of pulmonary metastases was counted. We could observe a trend towards decreased metastases in the cyclopamine group (~20%). On the other hand, remarkable side effects were caused by the cyclopamine/ethanol/triolein preparation (mainly skin ulcerations).