Cancer-induced bone diseases are often associated with increased bone resorption and pathological fractures. In recent years, osteoprotective agents such as bisphosphonates have been studied extensively and have been shown to inhibit cancer-related bone resorption in experimental and clinical studies. The third-generation bisphosphonate, ibandronate (BM 21.0955), is a potent compound for controlling tumour osteolysis and hypercalcaemia in rats bearing Walker 256 carcinosarcoma. We have studied the effect of ibandronate given as an interventional treatment on bone strength and bone loss after the onset of tumour growth in bone. Our results suggest that it is capable of preserving bone quality in rats bearing Walker 256 carcinosarcoma cells. Since other bisphosphonates have produced comparable results in man after their success in the Walker 256 animal models our findings suggest that ibandronate may be a powerful treatment for maintaining skeletal integrity in patients with metastatic bone disease

The effect of bisphosphonates on the mechanical properties of the uninjured contra-lateral cortical bone during fracture healing is poorly reported. There remains conflicting evidence with regards the effect of bisphosphonate therapy on cortical bone strength. We assessed the effect of nine weeks of Ibandronate therapy, in a dose known to preserve cancellous bone BMD and strength, on the mechanical properties of the uninjured rat tibial diaphyses using a standardised model of tibial osteotomy and plate fixation. Skeletally mature ex-breeder rats were used. Stress at failure of the tibial diaphyses was measured by a four-point bending test using a custom made jig for rat tibiae. The mechanical strength was compared with radiographic measurements of bone density. Animals received daily subcutaneous injections. 11 rats received 1μg/kg Ibandronate (IBAN) daily and 17 rats received 1ml 0.9% Sodium Chloride (CONTROL) daily. The IBAN group had a statistically significant, p=0.024, higher stress at failure 212.7 (±42.04) MPa compared to the CONTROL group 171.7 (±46.13)MPa. There was a positive correlation between the mechanical strength of bone and the radiological measure of bone density. Osteopenia is known to occur following a fracture even in the contra-lateral limb. This study demonstrates that ibandronate therapy has no detrimental effect and may even increase the strength of uninjured cortical bone during the fracture healing process. The longer term effect of ibandronate on cortical bone especially in relation to the accumulation of mico-damage requires further study. Bisphosphonate effect on the uninjured limb needs to be considered when reporting proportional strength of fracture repair compared to the uninjured limb

Fractures repair by two mechanisms; direct fracture healing and indirect fracture healing via callus formation. Research concerning the effects of bisphosphonate on fracture repair has solely assessed indirect fracture healing. Patients with osteoporosis on bisphosphonates continue to sustain fragility fractures. A proportion of osteoporotic fractures require plate fixation. Bisphosphonates impair osteoclast activity and therefore, may adversely affect direct fracture healing that predominates with plate fixation. Five skeletally mature Sprague-Dawley rats received daily subcutaneous injections of 1mg/kg Ibandronate (IBAN). Similarly, five control rats received saline (CONTROL). Three weeks following commencement of injections a tibial osteotomy was rigidly fixed with compression plating similar to that seen in routine clinical practice. Fracture healing was monitored with radiographs. Six weeks post plate fixation, animals were sacrificed. Radiographs were performed of the extricated tibiae following plate removal. The visibility of the osteotomy site was scored as totally visible, partially visible or absent as previously described. Mechanical testing was conducted on the healing osteotomies via 4-point bending. Fractures healed without visible external callus. In the IBAN group three animals had totally visible osteotomy lines and two had partially visible osteotomy lines. The CONTROL group had three animals with absent osteotomy lines and two with partially visible osteotomy lines. The mean (±SD) stress at failure for the healing tibial osteotomies at 6 weeks was 28.8 (±23.97)MPa in the IBAN group and 37.4(±29.20) MPa in the CONTROL group (p=0.62). Our results indicate that Ibandronate adversely affected direct fracture repair as demonstrated by the radiographic density of the fracture line. The strength of the repair was reduced but this did not reach statistical significance. Our results suggest that a sample size of 220 animals is required to detect a 15% difference (alpha 0.05, beta 0.2) which suggests the effect of bisphosphonates on direct fracture repair may be small

Objectives

Osteoporosis has become an increasing concern for older people as it may potentially lead to osteoporotic fractures. This study is designed to assess the efficacy and safety of ten therapies for post-menopausal women using network meta-analysis.