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Final Report Summary - FRACQUAL (Novel therapeutic agents to improve bone quality during fracture repair)

Novel therapeutic agents to improve bone quality during fracture repair - 293434 FRACQUAL

Despite using the most sophisticated treatment options, 10% of all bone fractures do not heal. The projects overall aims are to heal those fractures by mastering the biology behind the non-unions. This is achieved by adding new and potent bone-active and disease modulating drugs (e.g. Bone morphogenetic proteins (BMPs), bisphosphonate (BP) and different types of bone grafts and scaffolds). These are studied both in young and healthy animals as well as in old age bone and bone affected by osteoporosis. Secondly, new methods to evaluate the bone quality of the newly formed bone tissue are in focus. This is primarily based on use of synchrotron radiation techniques to evaluate e.g. bone composition, mineral structure and mechanical function of the tissue. These factors are essential to determine the treatments future potential.

The most important findings of the project so far are that when treating a long bone fracture in a young rats with a combination of BMP and bisphosphonate, more new bone is formed and this new bone construct is stronger than if these adjuncts are not used. This is true both when they are used as an adjunct to autograft or without autograft. Additionally, we have found that using allograft combined with the anabolic effect of BMP and the anti-catabolic effect of bisphosphonate is more efficient than when using autograft alone. These combinations may prove valuable in the treatment of non-unions. When comparing the response to these treatments in young and mature rats and in healthy rats and rats subjected to osteoporosis by ovarectomy, no major discrepancies were found. Thus, the efficacy of the treatments tested were equivalent in osteoporotic rats to that demonstrated in healthy rats, and similar between young and mature rats.

When treating bone fractures or critical size defects, novel bone grafts or scaffold materials in combination with growth factors may enhance new bone formation. The project found that a Collagen-Hydroxyapatite scaffold that has been used successfully in calvarial critical defect models was not able to promote bone healing in the more challenging environment of a rat long bone femoral fracture, prone to non-union as well as when using BMP alone. However, when the scaffold was combined with BMP, there was a tendency towards increased callus formation compared to BMP alone. The project also developed the first murine model of the induced membrane technique to treat critical size defects in the rat femur. A scaffold material based on tricalcium phosphate hydroxyapatite was tested alone or in combination with bone active drugs (BMP and bisphosphonates) to improve healing in a critical defect. The scaffold alone was not able to heal the defect, but when the synthetic scaffold was combined with BMP and combined a bisphosphonate, it improved the callus properties and enabled healing.

Moreover, small angle x-ray scattering (SAXS) to assess mineral structure and Fourier transform infrared (FTIR) microspectroscopy to assess local molecular composition has been developed and applied as methods of high interest to characterize the newly formed bone during healing. Osteoporosis induced by ovarectomy was found to induce an increased mineral crystal plate thickness in the trabecular bone in tibia and vertebra, whereas the molecular composition remained similar as in healthy rats. When investigating the local bone quality (molecular composition and mineral structure) of the newly formed bone surrounding a fracture, it was found that the callus tissue had a lower degree of mineralization, collagen maturity and degree of orientation of the mineral plates than the cortices. Also, the quantified elemental composition with Energy-Dispersive X-ray Spectroscopy (EDS) showed that the element compositions varied between the callus and the cortical bone. However, the different bone active drugs did not significantly alter the resulting molecular composition or the mineral crystal structure after 6 weeks of healing.

To continue develop methods to evaluate bone quality on a range of length scales, simultaneous small and wide angle X-ray scattering (SAXS/WAXS) investigate the variation in the mineral nanostructure between species, anatomical directions, and local variation across the cortex cross-section in the femur. The scattering data from all species reveals a remarkable similarity in the entire q range, which indicates that the nanostructure is essentially the same in all species. Small differences in the data from different directions confirm that the crystals are elongated in the [001] direction and that this direction is parallel to the long axis of the bone. A model consisting of thin plates was successfully employed to quantify the plate thicknesses in the range of 20–60 Å. Significant variation was found across the cross-section of the cortex in rats, where the crystal dimensions were lower and less organized in central cortex than in endosteal and periosteal regions. This was explained by the fact that rats lack haverisan remodelling, and that the bone in the central cortex was formed as part of the original mineralization during endochondral ossification. Taken together, these findings indicate the feasibility and importance of investigating the nanostructure and molecular composition to understand their contribution to bone quality and mechanical competence.

The project contributed to knowledge about the bone healing in general, and how to aging and osteoporosis affects the healing outcome. It evaluated existing and new combinations of bone grafts and bone active drugs to improve the new bone formation while controlling bone quality and reduce the complications of non-unions. The development of new therapeutic treatments to improve the amount and quality of the newly formed bone can decrease the number and complications of non-union and the associated morbidity. This has large socio-economic benefits since it would allow for patients to return to working life faster.

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